Open platform automated sample processing system

ABSTRACT

An automated sample processing system having a sample input adapted to simultaneously receive a number of sample containers, a reagent input adapted to receive one or more new reagent supplies, a consumable input adapted to receive one or more new consumable supplies, a solid waste output adapted to receive used consumable supplies, a liquid waste output adapted to receive one or more used reagent supplies, and a processing center. The processing center includes a decapper adapted to remove a lid from at least one sample container, an aspirator adapted to remove a specimen from the at least one sample container and transfer the specimen to an output vessel, and a capper adapted to replace the lid on the at least one sample container. The system also includes a sample output adapted to receive the output vessel, and a user interface adapted to receive an input from the user to indicate the identity of the at least one sample container, and control at least one operation based on a physical property of the at least one sample container.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. patent application Ser. No.12/062,950, filed Apr. 4, 2008, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/910,565 filed Apr. 6, 2007.This application is also related to U.S. Provisional Patent ApplicationSer. No. 61/183,857, filed Jun. 3, 2009. This application is alsorelated to U.S. Provisional Patent Application Ser. No. 61/113,855,filed Nov. 12, 2008, and U.S. Provisional Patent Application Ser. No.61/122,621, filed Dec. 15, 2008. This application is also related toU.S. Provisional Patent Application Ser. No. 61/185,081, filed Jun. 8,2009, entitled “Automated Human Papillomavirus Assay and System”(Attorney Docket No. 74708.000200). The present application claims thebenefit of, claims priority to, and incorporates herein by referenceeach of the foregoing references.

BACKGROUND

1. Field of the Art

The present disclosure relates to automated sample processing systems,and provides systems and methods that permit high-throughput specimenprocessing. Systems according to the invention may permit greatlyincreased sample processing throughput, decrease the number of samplesthat can not be assayed because of inadequate sample volume for assaydetection, decrease the need for manual labor and allow for productiveuse of an operator's “walk-away time” during sample processing. Aspectsof the disclosed systems may be used independently or in other systems.

2. Description of Related Art

Historically, biological samples being tested in the context of medicalservices have been processed using labor-intensive manual methods, orsemi-automated methods requiring careful supervision by a laboratorytechnician. Such systems can be prone to operator error in many forms,such as improper testing (e.g., using an improper reagent or mis-readingthe results), sample loss (e.g., spilling a sample), and identity loss(e.g., losing the patient name or associating the sample with theincorrect patient). While semi-automated methods may help reduce laborcosts and operator error, many automated systems are cumbersome to use.For example, many “automated” systems are actually only semi-automated,and may require labor-intensive pre-processing steps to transfer theinput samples into a format, such as a particular sample container, thatthe machine can accept. Others perform a subset of processing steps butrequire an operator to manually perform the others. It has also beenfound that existing semi-automated systems may lack safety controls,require frequent stopping for service, operate inefficiently or slowly,or have other problems or shortcomings.

There exists a need in the art for alternative automated andsemi-automated processing systems, processing systems that can acceptsamples in various formats, and processing systems that cansimultaneously process different kinds of samples. There also is a needfor alternative sample processing methods. There also is a need foralternative sample processing equipment and sub-systems that may be usedto assist with sample processing tasks in fully-automated,semi-automated and manually-operated systems.

SUMMARY

In one aspect, there is provided an automated sample processing systemhaving a sample input adapted to simultaneously receive a number ofsample containers, a reagent input adapted to receive one or more newreagent supplies, a consumable input adapted to receive one or more newconsumable supplies, a solid waste output adapted to receive usedconsumable supplies, a liquid waste output adapted to receive one ormore used reagent supplies, and a processing center. The processingcenter includes a decapper adapted to remove a lid from at least onesample container, an aspirator adapted to remove a specimen from the atleast one sample container and transfer the specimen to an outputvessel, and a capper adapted to replace the lid on the at least onesample container. The system also includes a sample output adapted toreceive the output vessel, and a user interface adapted to receive aninput from the user to indicate the identity of the at least one samplecontainer, and control at least one operation based on a physicalproperty of the at least one sample container.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an isometric view of an exemplary automated sample processingsystem according to one embodiment of the invention.

FIG. 2 is a schematic top plan view of the embodiment of FIG. 1, withthe bottom of the figure corresponding to the front of the machine.

FIG. 3 is a schematic diagram of an exemplary assay protocol that may beconducted using the embodiment of FIG. 1.

FIG. 4 is an isometric partial view of the sample intake and initialtransfer area of the embodiment of FIG. 1.

FIG. 5 is a cross-section side elevation view of a portion of anexemplary embodiment of a sample rack.

FIGS. 6A and 6B are isometric partial views of a barcode reader, shakerunit and decapper/capper unit shown in the decapping position in FIG.6A, and the aspirating position in FIG. 6B.

FIG. 7A is an isometric view of an exemplary bellows gripper for use inone embodiment of a DCU.

FIG. 7B is an isometric view of an exemplary gripper that may be usedwith a DCU, shown addressing two different size bottles.

FIG. 7C is an isometric view of an exemplary combined shaker andtransport mechanism.

FIG. 7D is an isometric view of an exemplary combined aspirator/reagentpump.

FIG. 8 is a schematic diagram of a DCU flowpath.

FIGS. 9A-9C are schematic diagrams of a DCU system showing variousaspects of its operation and capabilities.

FIGS. 10A-10F are schematic diagrams of a DCU system showing variousaspects of its operation and capabilities.

FIG. 11 is an isometric view of an exemplary extraction tube unit.

FIG. 12 is an isometric view of an exemplary extraction tube unitgripper.

FIG. 13 is an isometric view of an exemplary extraction tube unittransport mechanism.

FIGS. 14A and 14B are side elevation views illustrating exemplaryconfigurations of magnets located adjacent an extraction tube unit.

FIG. 15A is a side elevation view of an exemplary aspirator.

FIG. 15B is a side elevation view of an exemplary aspirator stationemploying the aspirator of FIG. 15A.

FIG. 16 is a side elevation view of an exemplary four-channel,fixed-separation pipettor.

FIGS. 17A and 17B are cross-section side elevation views of the pipettorof FIG. 16 shown before being fully inserted into an ETU in FIG. 17A,and after being fully inserted in FIG. 17B.

FIG. 18 is an isometric view of a manipulation system for an exemplaryfinal transfer unit including the pipettor of FIG. 16.

FIGS. 19A-19D are schematic drawings illustrating two exemplary finaltransfer operations between an ETU and a sample tray.

FIG. 20 is a schematic top plan view of alternative embodiment of aprocessing system.

FIG. 21 is an isometric view of another exemplary ETU transportmechanism.

FIG. 22 is a flow diagram illustrating an exemplary assay protocol.

FIGS. 23-25 are charts illustrating the results of an exemplary assayprotocol.

FIG. 26 is a partial isometric view of an exemplary embodiment of anopen platform DCU.

DETAILED DESCRIPTION

The present disclosure provides various exemplary embodiments ofautomated or semi-automated sample processing systems, methods forautomated, high-throughput sample processing, control systems forcoordinating and controlling the operations of a high-throughputspecimen processing systems, and various devices that may be used in theforegoing sample processing systems or in other processes, devices orsystems. Preferred embodiments of the invention may provide faster, morereliable, and cheaper methods and machines for high-throughput patientsample processing, but other benefits may be realized instead of or inaddition to these.

As noted above, exemplary embodiments of these systems may providegreatly increased sample or specimen processing throughput. For example,one embodiment of a system described herein may process about 1,400biological samples through a ten-step protocol during a single 8-hourshift, producing purified DNA in a convenient 96-well format from animalcells provided in standard sample collection tubes. Another exemplaryembodiment of an automated system may generate up to 2000 clinicalresults per 8-hour shift. Embodiments of the invention also may decreasethe need for manual labor and allow productive use of an operator's“walk-away time” during sample processing. For example, walk-away timemay be increased and efficiently used by providing large reservoirs ofrequired materials (including samples), as well as by providingcontinuous or periodic access to inputs and outputs. These featuresallow flexible time windows for re-stocking the machine, allowing themachine to operate at full capacity while the operator attends to othertasks until required to resupply or remove completed samples from themachine during a restocking window.

In other aspects, embodiments of the invention may provide improvedextraction of a sample volume from a tube or vial containing the sampleduring high throughput processing. This may result in fewer incidencesof samples that can not be analyzed due to inadequate sample volumebeing available for detection, which, in turn, minimizes the need tocollect additional samples from patients. Still further, embodiments mayuse unique sample processing logic to avoid unnecessarily processingsamples that have too little volume to test reliably.

The systems described herein can be used to perform steps required inmany common clinical or research laboratory methods. Exemplaryembodiments can be used with a DNA analysis assay, such as the NextGeneration Hybrid Capture® High Risk assay developed by Qiagen GmbH ofHilden, Germany (“Qiagen”). This assay may maintains high clinicalsensitivity for high grade cervical disease established by the HybridCapture 2 during numerous large scale clinical studies, while creating ahighly specific result. Examples of this and other assays that can beperformed by embodiments of the systems described herein are disclosedin U.S. Provisional Applications Ser. No. 61/231,371, filed Aug. 5,2009, entitled “METHODS AND KITS FOR ISOLATING NUCLEIC ACIDS USING ANANION EXCHANGE MATRIX” and 61/147,862, filed Jan. 28, 2009, entitled“SEQUENCE SPECIFIC LARGE VOLUME SAMPLE PREP SOLUTION UTILIZING HYBRIDCAPTURE TECHNOLOGY,” which are incorporated herein by reference in theirentireties.

It will be understood that the foregoing assays are exemplary and thatthe subject system may be used for performing other clinical processesor detecting other moieties such as other nucleic acids, proteins, smallmolecules, cells, viruses and the like. Indeed, while laboratoryprotocols are often quite diverse in their particular steps, manygenerally rely on various common underlying operations, such as theaddition of reagents, mixing, incubating, and so on. Embodiments of theinvention described herein may be adapted to provide the ability toperform a diverse set of common laboratory operations in a standard tubeformat, with different systems readily constructed from combinations ofprocessing stations to perform steps required in virtually any protocol.The systems provided herein may be utilized, for example, forhigh-throughput preparation of DNA, RNA, protein, plasmids, chromosomes,antibodies, or organelles. Other systems may be used to perform all orpart of methods such as: transformation; mating (e.g., of yeast,nematodes, or other small organisms); cloning; dot blotting (for DNA,RNA, protein, enzyme, etc.); mutagenesis; preparation for sequencing;nucleic acid amplification; primer synthesis; ELISA; enzyme assays;X-gal staining; immunohistochemistry; immunofluorescence; sample fixing;flow cytometry; in-situ hybridization; in vitro transcription and/ortranslation; sample purification from agarose; peptide synthesis;combinatorial library preparation; and so on. Processes usingembodiments of the invention may employ samples of virtually any originincluding, for example: prokaryotic cells; eukaryotic cells; tissuesamples from multicellular organisms; whole organisms (e.g., flies,worms, or other similarly small organisms); conditioned media;environmental samples; and so on. Exemplary protocols that may beperformed include those shown in the texts “Molecular Cloning: ALaboratory Manual” (Third Edition, Cold Spring Harbor Press) or“Condensed Protocols From Molecular Cloning: A Laboratory Manual” (FirstEdition, Cold Spring Harbor Press), the disclosures of which are herebyincorporated by reference in their entireties. Further, embodiments ofthe invention may be adapted to provide any suitable output format, inaddition to the 96-well and 384-well formats described below, such asoutputs to a membrane or blotting paper, bacterial, yeast or mammaliancell culture plate, and so on.

Referring now to FIGS. 1 and 2, an exemplary embodiment of an automatedsystem in the form of a pre-analytic system (“PAS”) 100 is described indetail. FIG. 1 is an isometric view of the PAS 100 showing the devicewith its exterior coverings in place. FIG. 2 is an overhead schematicview of the PAS 100, in which some features are partially or fullyobscured by items located above those features, but their location andoperations still will be clear from the Figures and followingdiscussion. This embodiment of a PAS 100 extracts DNA from patientsamples, such as cervical samples taken from a so-called “pap smear,”cervical cell samples taken into a sample collection medium such as thatdescribed in provisional application 61/108,687 filed Oct. 27, 2008(which is incorporated by reference herein), or any other source ofpatient cells.

The PAS 100 or other embodiments of a pre-analytic system may be used inconjunction with an analytical system that analyzes or tests the samples(such as by analyzing DNA that may be present in the sample). Forexample, an exemplary analytical system may be capable of carrying outthe steps of a nucleic acid detection assay such as those described inQiagen's Hybrid Capture 2 assay or Next Generation Hybrid Capture® Assayprotocols. Such steps may include sample loading, target nucleic aciddenaturation, probe hybridization, target capture, signal production,signal detection and assay result reporting. An exemplary analyticalsystem that may be used to perform these or other assays is theQIAensemble JE2000, available from Qiagen.

A central control unit (CCU) may be used to control and/or monitor thePAS 100 and/or a downstream analytical system, and an exemplary CCU mayprovide a processing interface between the PAS and the analyticalsystem. For example, a CCU may be combined with a PAS and an analyticalsystem to perform all of the steps necessary to pre-process and test asample according to the Hybrid Capture 2 or Next Generation HybridCapture® protocols.

The exemplary PAS 100 is a generally self-contained unit having variousinput and output locations at which an operator can provide supplies andremove waste and processed samples. In the exemplary embodiment, the PAS100 includes a sample rack input 102, a sample rack output 104, acontrol vial and reject vial access point 106, a first pipette tip input108, an ETU input 110, reagent trays 112, a second pipette tip input114, a sample plate input 116, a sample plate output 118, and one ormore solid waste outputs 120. The functions of these various inputs andoutputs are described in more detail below. The PAS 100 also may includea suitable electrical interface (not shown) for connecting to a CCU thatcontrols the device. Of course, the CCU, or various parts of it, may beintegrated into the PAS 100 itself, in which case the PAS 100 may beprovided with a human interface to receive operating instructions and/ordisplay system status. Such an interface may include various interfaceelements known in the art, such as a monitor, touch-screen monitor,keyboard, mouse, microphone, speaker, barcode reader, and so on. Whilethe shown arrangement of inputs and outputs has been selected for thisembodiment, it will be understood that other arrangements may be used inother embodiments.

The exemplary PAS is adapted to process biological samples, includingliquid-cased cytology (LBC) samples into standard 96-well platescontaining the extracted sample nucleic acid. During processing, thesamples are taken from standard sample containers, and processed in astrip of test tubes, called the extraction tube unit (“ETU”). An exampleof an ETU is described below in detail with respect to FIG. 11. Each ETUmay have any suitable number of test tubes, but in one embodiment theETU has eight test tubes to conveniently correspond to a row of a96-well plate.

Exemplary System Preparation

The PAS 100 is prepared for operation by loading it with samples to beprocessed, and consumable elements, such as pipette tips 202, 204,reagents 206, sample plates 208, and ETUs 210.

In the shown embodiment, the pipette tips 202, 204 are loaded into thefirst and second pipette tip inputs 108, 114. The pipette tips 202, 204may be provided in any suitable form or carrier. In the shownembodiment, the pipette tips 202, 204 are provided in racks that eachhold multiple tips 202, 204 in a vertical orientation to facilitatetheir retrieval by an automated pipettor. Multiple pipette racks, whichare represented by rectangles in FIG. 2, may be loaded into the PAS 100at one time, and advanced to the automated pipettor location byconveyors, robot arms, or other suitable devices as known in the art. Inthis embodiment, the pipette tip inputs 108, 114 comprise simplerectangular openings that feed into the pipette rack conveyors. Ifdesired, doors or other covers may be provided over these openings. Theracks may be deposited into one or more solid waste containers 214 onceall of the pipettes are removed. In addition, used pipettes may bedeposited in the racks before they are discarded to minimize solid wastevolume.

Reagents 206 are loaded into one or more reagent trays 112. The trays112 may be mounted on racks to slide out from the front of the PAS 100to facilitate loading and unloading. In addition, each tray 112 may holdmultiple reagent bottles, which are connected to fluid lines to conveythe reagents to the necessary locations. If necessary, the trays 112 mayinclude clamps, straps, or appropriately-sized pockets to hold thebottles in place. As used in this context, the reagents may comprise anyfluid or other material that is used in the processing steps undertakenwithin the PAS 100, such as chemical solutions, deionized water, lysis,buffers, oils, capture bead suspensions, and the like.

Sample plates 208, such as standard 96-well sample plates known in theart, are loaded into the sample plate input 116. In the shownembodiment, multiple sample plates 208 are stacked on top of each otherat the sample plate input 116. During operation, the lowermost plate 208is advanced to a sample plate loading position 212 by a conveyor orother suitable means. Once filled, the sample plate 208 is returned tothe sample plate output 118, and added to the bottom of a stack ofpreviously-filled sample plates 208. The filled sample plates 208 areraised upwards to the sample plate output 116, where they are retrievedby an operator.

ETUs 210 are loaded into the ETU input 110. The ETU input 110 leads toan ETU rack that holds the ETUs. Conveyors or robot arms advance theETUs 210 to a first position at which the ETUs 210 are filled, and asecond position at which they are removed from the rack and conveyed forfurther processing. As explained below, the ETUs comprise may beconstructed to facilitate their movement along a conveyor or by arobotic arm or other mechanism.

Samples are introduced into the PAS 100 by loading them into a samplerack 201 (FIG. 2), and sliding the sample rack 201 into the sample rackinput 102. The sample rack 201 is moved by a conveyor from the samplerack input 102 to a processing location 216, and then back to the samplerack output 104 located below the sample rack input 102. Any suitableconveyor system may be used for this purpose. For example, a conveyorbelt, robotic arms, or powered rollers may be used to move the sampleracks 202 laterally, and an elevator may be used to lower the sampleracks 202.

As shown in FIG. 2, as number of sample racks 202 may be loaded in thePAS 100 at any given time. While it would be possible to scaleembodiments such that the rack 202 includes only a single sample (or tosimply eliminate the rack and use the original sample container as thesample carrier), higher productivity is likely to be achieved byincluding a number of samples on each rack. In one embodiment, eachsample rack 201 may include forty-two or forty-eight sample positionsarranged in a rectangular array. Where the number of sample positions isincreased, it may be necessary to provide greater accuracy to theequipment (such as a robotic arm) used to extract the sample containers.In addition, each sample position may be configured to hold samplecontainers of one or more different sizes, which is particularly helpfulwhere the PAS 100 is used to process samples that typically come fromvarious different sources. As one example, the sample rack 201 may beadapted to hold sample vials typically used in the known PreservCyt,SurePath, and/or DCM testing kits.

Exemplary Processing Overview

The PAS 100 processes the samples generally along a path designated bythe dotted arrow line. There are three general processing stages: aninitial transfer stage in which each sample is transferred to aprocessing vessel (and in which some other processing may occur), asecond stage in which the samples are analyzed or processed into ananalyzable format, and a final stage in which the samples aretransferred to a standardized output vessel. The output vessel—hereshown as an exemplary 96-well plate—may then be removed and analyzed.

In a preferred embodiment, the PAS 100 uses a processing system in whichthe various steps are timed according to a repeating, fixed-lengthinternal clock cycle. The clock cycle may be arbitrary, or it may bebased on processing parameters, such as the durations of particularprocessing steps. For example, if one processing step takes 100 seconds,with transport time to that step taking 20 seconds, and the remainingprocessing steps can be completed within that 120-second time frame or amultiple of that time frame, the clock cycle may be set at 120 seconds.In the exemplary embodiment, the clock cycle is about 150 seconds (2½minutes). In this embodiment, each process or combination of processesgenerally occurs during one full clock cycle or a multiple of the clockcycle time. In most cases, each ETU is moved to the next processing steponce per clock cycle. In some instances, a processing step can becarried out over multiple clock cycles, which may be accommodated byhaving multiple stations able to perform the same step in parallel. Itwill be appreciated that some variation in the execution time of eachstep may exist due to transport times, and some processes may take lessthan a full clock cycle and sit idle until the next process begins. Itwill also be understood that the clock cycle may be universal across allprocessing stations (that is, the clock cycle at each station ismeasured based on a single universal timer), or the clock cycle may berelative at each station (for example, the clock cycle at each stationmay begin once a sample is placed in it). The latter system may beuseful where transportation times occupy a significant portion of theclock cycle, which may be the case where a single ETU transportmechanism is used. Using the foregoing system, throughput can beincreased by processing multiple samples in a parallelmanner—simultaneously performing each processing step on multiplesamples. The processing steps may be grouped with similar steps tocreate processing stations or modules, which may improve efficiency andreduce system size.

In the initial stage, the samples, provided in the sample racks 202, aremoved towards a transfer station having a barcode reader 218, a mixingunit 220, and a decapper/capper unit 222. Each sample is processed atthe first transfer station, as shown by arrow segment A2, by removingthe sample container from the sample rack 201, reading a barcode on thesample container using the barcode reader 218, mixing the samplecontainer in the mixing unit 220 to homogenize the contents, anddecapping the sample container at the decapper/capper unit 222. Next, anautomated pipettor (not shown) transfers an aliquot of sample from thesample container to an ETU 210. When it is full, the ETU 210 is advancedto a transfer unit 224 that moves the ETU from the ETU rack into aprocessing area 226.

In the shown embodiment, the processing area 226 comprises one or moreprocessing stations. The type and number of processing stations may varydepending on the particular use for which the PAS 100 is employed. Forexample, the processing area 226 may include a sample adequacy station228, a first mixing station 230, a first incubation station 232, asecond incubation station 234, a second mixing station 236, a firstaspiration station 238, a second aspiration station 240, and a finaltransfer station 242. Stations may include multiple ETU receptacles orbe duplicated to permit an operation to continue across multiple clockcycles, as further described below. The processing stations may beprovided in a row within a single continuous chamber. This arrangementmay simplify the construction or operation of the PAS 100 in variousways. For example, is may be possible to use a single transportmechanism, such as a robotic arm, to move the samples along theprocessing stations. Also, access to all of the processing stations maybe conveniently available from the back of the machine. While theforegoing linear arrangement is believed to provide certain benefits, itis not required in all embodiments, and in other instances acarousel-like arrangement or other arrangements may be used.

The use of a fixed clock cycle and the various input and output featureson the PAS 100 enable continuous operation with relatively little userinput. During operation, samples are periodically added at the samplerack input 102, and processed racks are removed from the sample rackoutput 104. Four racks may be loaded into the device for processing, andthere is space for three processed racks. Without user intervention,processing may stop once a fourth rack is completed processing (althoughprocessing may continue for a short while even after the fourth rack iscompleted by providing an access arm that obtains samples from a fifthrack, as explained below). Thus, the exemplary embodiment can be said tooperate on a four-rack service interval. All four processed racks may beremoved during servicing to permit continuous operation to process fourmore racks without intervention. To minimize the amount of service timenecessary to operate the system, it may be possible to load the PAS withsufficient supplies of reagents, pipette tips, ETUs and sample trays toprocess four or more full racks before requiring further service. Inaddition, throughout operation, solid and liquid waste containers 214,250 receive expended pipette tips, ETUs, ETU racks, aspirated liquids,and so on. The sizes of these containers may be selected to beapproximately filled during the four-rack service cycle, but other sizesare possible.

While the foregoing features may be provided in some embodiments, theuse of convenient access points preferably permits a user tocontinuously add supplies and remove waste at virtually any time duringoperation. This maximizes the ability to service the device whileperforming other tasks while the machine operates. Input racks may beadded and removed as samples are processed. As the system processes aninput rack in approximately 15 minutes, additional racks may be added(and completed racks removed) at any time between 15 minutes and 1 hourafter operations commence, allowing greater utilization of walk-awaytime. Two control holders and two reject holders permit operations tocontinue even when user attention is required, as one control holder maybe filled (or reject holder emptied) while the other is kept availablefor use. Embodiments also may employ a visual indicator to show whenattention to a control or reject holder is required, and can lock thecontrol or reject holders or other access points to prevent user accessof a holder that is reserved for use or prevent access when internaloperations are being performed at the access point.

Various sensors may be used to detect the quantity of supplies, and suchinformation may be displayed on a user interface or otherwisecommunicated to an operator. For example, ultrasonic sensors or otherdevices known in the art may detect the number of pipette tips, ETUs,and output plates available, and the levels of solid and liquid wastes,and report these levels to the control unit. In order to preventunnecessary stops during processing, the control unit can be programmednot to permit sample processing to begin unless sufficientsupplies/waste capacity are available for processing to proceed tocompletion. A visual indicator may be used to show levels of supplies,waste, and input samples. Optionally an audible alarm may be sounded towarn of critically low levels of supplies, and/or to warn of cessationof operations due to low reagent levels or malfunctions. The audiblealarm may include voice prompts to help identify the fault or specificsupplies needed.

As with the other consumables, one or more of the reagents may bemonitored by sensors to detect their levels. The reagents may be addedin containers, with a siphon extending down into each reagent container,and pumps to draw reagents to on-board reservoirs. Liquid level sensorsdetermine the amount of reagent present in each reservoir, allowing thecontrol system to only begin processing a sample when sufficientreagents are on-board for complete processing. Additionally, theon-board reservoir acts as a “bubble trap” because any air that entersthe transport line between a reagent container and its reservoir willfloat to the top of the reservoir and not be drawn into the dispensingsystem, which uses a separate inlet in the reservoir and an associatedpump to draw fluid from each reservoir. The use of an intermediatereservoir also allows reagent bottles to be changed without interruptingthe reagent supply to the PAS. In some cases, certain reagents mayrequire periodic mixing. For example, some reagents containingmacroscopic particles (e.g. capture beads, solid catalysts, etc.) thatare prone to settling and/or forming clumps may need to be mixedperiodically. The system keeps such reagents sufficiently mixed byrecirculating the reagent between its reservoir and reagent container orwithin the reservoir itself. Additionally, when the system is expectedto be inactive for a period of time (e.g., at the end of a shift, formaintenance, etc.) such reagents can be pumped out of the dispensinglines back into their input container. High cost reagents are likewiseconserved by being pumped back into their input container when thesystem is expected to be inactive for a period of time.

Processing Example

An exemplary embodiment of a processing method is now described withreference to FIGS. 2 and 3A-3F. While the following processing methodhelps explain the processing operation of one exemplary PAS 100, as wellas the operation of the foregoing exemplary processing stations, it willbe understood that it does not limit the disclosure in any way.

In the embodiment of FIGS. 3A-3F, the PAS 100 is configured to performtwo different assay protocols: the “PC” and the “Surepath” protocol.These protocols are intended to prepare the samples to be tested for thepresence of human papilloma virus (“HPV”) DNA. In this embodiment, twoprotocols are used because the samples may be provided in differentbottles and/or mediums.

Beginning in step 302, a sample container is removed from a sample rack201 by a robotic arm or other suitable mechanism. In some cases, such aswhere it may be desired to verify test results or system operation, thesample container may instead be removed from a control sample rack 244that holds a number of control samples. In step 304, a barcode reader218 reads a barcode on the sample container to identify and/or track thesample. If no barcode is present or the barcode does is not associatedwith a patient or otherwise recognized by the system, the samplecontainer may continue through processing or, more preferably, beremoved to a reject vial rack 246 as shown by step 305. The reject vialrack 246 must be manually emptied by the user, which helps ensure thatfailures are noticed by the operator and any appropriate follow-upaction is taken. Samples can be rejected for many reasons, including:quantity not sufficient (QNS), unable to remove cap, barcode unreadableor not recognized, etc. For example, unremovable caps may be manuallyloosened or the sample transferred to another container; samples havingunrecognized or unreadable barcodes can be manually identified; and QNSsamples may be manually processed (optionally with addition of an agentthat facilitates sample extraction) or may be reported to a careprovider or patient as having been unassailable.

In step 306 the sample is mixed to homogenize the contents of the samplecontainer. The samples can be mixed or agitated by various methods anddevices known in the art, and it is not necessary to explain the detailsof such mixing means here. Examples of shakers include orbiting shakers,vertical shakers, inversion shakers (suitable for closed samplecontainers), platform shakers, combination shakers (e.g., shakerssimilar to those used as commercial paint mixers), paddle-style mixers,vibration mixers, ultrasonic mixers, and any combination thereof. Themeans of agitation may vary on factors such as the shape of thecontainer in which the sample is held, the nature of the specificsamples being analyzed and the moiety therein which is being detected.

In step 308, the cap is removed from the sample container. If the capcan not be removed, the sample container is removed to the reject rack309 and addressed as noted above. With the cap removed, a specimen ofany suitable size (e.g., 2000 ul in the PC protocol and 1500 ul in theSurepath protocol) is removed from the sample container in step 310. Instep 312, this specimen is dispensed into a test tube for furtherprocessing. After the sample is removed, the cap is returned to thesample container, and the sample container is replaced on the samplerack 201, preferably to its original position. Any suitable device maybe used to transfer the specimen to the ETU. For example an automatedpipetting system such as those available from STRATEC Biomedical SystemsAG of Germany may be used. As noted above, the test tube may be part ofan ETU having multiple tubes, but any other suitable vessel may be usedto hold the specimen in other embodiments.

In the exemplary embodiment, the ETU has eight test tubes, and thereforeaccommodates eight samples. As explained below, each ETU is processeddownstream according to the exemplary 150-second clock cycle. As such,steps 302, 304 and 308 are conducted eight times during each clock cycle(i.e., once every 18.75 seconds) so that the ETU is filled and movedinto place to be ready as each clock cycle begins. Of course, thesesteps may occur more quickly, provided a delay is included to preventthem from exceeding the rate at which the remaining operations occur.

Next, the ETU containing the specimen is placed in the sample adequacystation 228, where it is tested in step 314 to determine the adequacy ofthe sample for further processing. In an exemplary embodiment, step 314,including transportation to the sample adequacy station 228 may takeapproximately one full 150-second clock cycle to complete. Any suitablesample adequacy testing device may be used. For example, the sampleadequacy station 228 may comprise an optical measuring system, in whichthe turbidity of the sample is optically measured to determine whetherthe sample contains an adequate amount of cells. One example of such adevice is shown in U.S. application Ser. No. ______, entitled “EnsuringSample Adequacy Using Turbidity Light Scattering Techniques” and filedon Oct. 9, 2009 (also identified as Attorney Docket No. 74708.000601),which is incorporated herein by reference in its entirety. An exemplaryturbidity measurement preferably is performed within about ten minutesof after the sample is dispensed in the ETU to prevent inaccuracy thatmay be caused by the sample settling. Optionally, the ETU may beagitated, such as by the device that moves it to the sample adequacystation 228, or by a shaker mounted to the station 228, to help ensurean accurate turbidity measurement. Turbidity also may be measured againafter an interval of time to determine how much of the turbidityinitially measured is due to classes of non-cellular material with adifferent (faster or slower) settling profile than cells (e.g., hair,mucus, bacteria), which may provide greater sample accuracy assurance.If it is determined that the sample is not adequate for further testing(e.g., too few cells are present in the sample), the PAS 100 controlsystem may flag the sample in step 315. Flagged samples may continue tomove through the processing area 226, but reagents will not be depositedinto the sample to prevent the unnecessary waste of valuableconsumables. For simplicity, however, an inadequate sample may simplyprogress as if it were an adequate sample, but the results will be notedas being based on an inadequate sample. In other embodiments, if thesample adequacy measurement indicates that a sample containsinsufficient cells, the system may be configured pipette the sample backto its original container and move the container to the reject rack 246.

In step 316, the ETU 210 containing the samples is moved to the firstmixing station 230. The first mixing station may have two separatesubstations, 230 a, 230 b, each of which is sized to hold one ETU. Itwill be understood that, in other embodiments, the first mixing stationmay have a single station, or more than two substations. The substations230 a, 230 b may be separate from one another, but preferably areconnected to a common platform and a single shaker unit. The ETU ispositioned in the first sub-station, where suitable amounts of a firstreagent (60 ul for both protocols) and a buffer (1000 ul for the PCprotocol and 1200 ul for the Surepath protocol) are added to thesamples, and the samples are is mixed (e.g., for 15 seconds at 1000rpm). While still in the first sub-station 230 a, a second reagent maybe added (e.g., 25 ul), and the sample may be further mixed (e.g., 30seconds at 1000 rpm). The ETU remains in the first substation 230 a forone full clock cycle (less time necessary for transport). Any suitableagitator or shaker unit may be used at the mixing station 230 to mix thesamples. Examples of such devices are described briefly above, and neednot be described here.

In step 318, the ETU is moved to the second substation 230 b of thefirst mixing station 230. Here, the samples are mixed (e.g., for 15seconds at 1000 rpm), a third reagent may be added (none for the PCprotocol, and 100 ul of a third reagent for the Surepath protocol), andthe samples are mixed again (e.g., for 30 seconds at 1000 rpm). The ETUremains in the second substation 230 b for one full clock cycle (lesstime necessary for transport). It will be understood that it is notstrictly necessary to move the ETU from the first substation 230 a tothe second substation 230 b in all embodiments.

One or more dispensers, such as a movable dispensing unit 248, may beprovided to add the buffers and reagents to the samples in substations230 a, 230 b. The dispensing unit 248 may be controlled to dispense thecorrect amount of reagents or buffers in accordance with the type ofsample located in each test tube along the ETU. Reagents can bedispensed through fluid systems using pumps, pistons, and other meansknown in the art. Reagents can be dispensed through a nozzle that is incontact with a liquid sample into which it is to be dispensed, in whichcase it may be desirable for the nozzle to be disposed of or be washedbetween dispenses into different samples, thereby decreasing samplecarryover. Reagents can also be dispensed in drops or streams from anozzle not in contact with the sample. The nozzle may have an openingwith a diameter less than or equal to the diameter of the fluid transferlines that transport the sample to the nozzle. Optionally the nozzle maysimply be a continuation of the fluid transfer line. The nozzle may bemade of a hydrophobic or superhydrophobic material, whereby droplets ofsample are prevented from clinging to the nozzle and dispense locationand volume are better assured. Reagent dispensers can be single-channelor multi-channel, for example, permitting a reagent to be dispensed inparallel into multiple containers. The details of such dispensers areknown in the art, and no explanation of the same is necessary here.

In some embodiments, it may be desirable to dispense reagents containingmacroscopic particles (e.g., capture beads, solid catalysts, etc.) intothe sample. Macroscopic particles can be difficult to accurately andconsistently dispense due to their tendency to become stuck indispensing lines and on nozzles. To help address these potentialdifficulties, in one embodiment the PAS 100 may dispense a macroparticlesuspension (for example, 60 ul) into the dispensing line for alarger-volume reagent that is added in the same processing step (forexample, 1000 ml or 1200 ul of buffer). This helps flush themacroparticles through the dispensing line and ensure that the correctvolume of beads is added. This methodology also may help prevent themacroparticles from drying out which could otherwise cause stickinessand clumping, leading to inconsistent results or machine downtime. Inthe embodiment shown, the first reagent may comprise 60 ul of fluidhaving a suspension of macroscopic capture beads. To obtain accuratedispensing of this fluid, the dispensing arm 248 may be positioned atthe desired ETU position, and then the macroscopic particle suspensionis dispensed into the buffer flow path at a simple T-junction (i.e., thesuspension is injected generally at a right angle to the straight bufferflow path). The macroscopic particle suspension may be injected beforethe buffer flow begins, which may cause some of the buffer in the flowpath to flow out of the dispensing nozzle. Once the suspension is in theflow path, the relatively large volume of buffer is dispensedhorizontally through the T-junction, flushing out the beads anddispensing them into the ETU. As the reagent volume is larger than thevolume of the flow path, the beads are completely dispensed into theETU. In the embodiment shown, the flow path may be lined with Teflon™(polytetrafluoroethylene) to help prevent the macroparticles fromsticking.

Of course, other methods may be employed to introduce the macroparticlesinto the larger volume reagent path. For example, the macroparticles canbe added via an injection loop of a standard HPLC injector which is thenrotated to be in line with the buffer dispensing line; or they can beadded to the dispensing line through a controlled or one-way valve.Because the macroparticle suspension is added to another reagent, it canbe dispensed through a shorter path than if it were added directly tothe samples; thus, the length of tubing dedicated to the macroparticles(which may require more frequent maintenance or replacement than theremainder of the system due to macroparticle accumulation or clogging)is decreased.

If desired, a system may be provided at the first mixing station 230 (orat any other stations at which fluid is added to the samples ormeasurement of the sample volume may be helpful) to help ensure that thereagents are fully dispensed into the ETUs. For example, one or moreultrasonic rangefinders may be used to measure the fluid levels in theETU tubes after the reagents are dispensed therein. Such devices arewell-known in the art and need not be described here. If the fluid levelof any sample is found to be higher or lower than a predeterminedtolerance range, an alert may be raised and the sample may be flagged asdescribed above in step 315. If the fluid levels in a number of ETUtubes is deficient or otherwise outside a predetermined tolerance range,this may indicate a supply loss or problem with the supply lines, andthe system may initiate a failure mode in which processing of additionalsamples is halted (although the system may be configured to continueprocessing samples that have adequate reagent volume to completion or tosome predefined safe stopping points). The system may also be programmedwith a feedback system to attempt to add reagents to under-filledsamples (provided the type of missing reagent can be determined), or toactively measure the fluid level during dispensing to ensure proper filllevels during the dispensing process.

In step 320, the ETU is moved to the first incubation station 232, wherethe samples are incubated for a suitable time (e.g., 10 minutes at 60degrees Centigrade for both protocols). As shown in FIG. 2, the firstincubation station 232 may include multiple cells or substations, eachof which can hold an ETU. Multiple cells are provided because the ETUsremain in the first incubation station 232 four times longer than the150-second clock cycle. Thus, providing at least four cells allows ETUsto be inserted into and removed from the first incubation station 232every 150 seconds, while each ETU is still properly incubated for 10minutes. As shown, the first incubation station 232 may include one ormore extra cells. If greater incubation time is desired, a greaternumber of positions in the heating block may be employed to providesufficient space to accommodate ETUs for the corresponding number ofclock cycles. Furthermore, assuming the incubation time remains 10minutes, the addition of extra cells also allows the rest of the systemto operate at faster clock cycles; for example, adding one extra cell,as shown, permits a 120-second clock cycle for the rest of the system.

The first incubation station 232 may use any suitable heating system toincubate the samples. For example, the first incubation station 232 maycomprise one or more aluminum or steel heating blocks having cutoutsthat match the shape of the ETU and into which the ETU test tubes snuglyfit to receive heat from the block. The heating blocks may be heated byelectric resistance heaters or other means. In a preferred embodiment,the heating blocks ensure temperature uniformity within about one degreeof the set point even as ETUs are being installed and removed. This maybe accomplished by using feedback control mechanisms to control thetemperature of the heating block, by providing insulation surroundingthe heating blocks, by providing sufficient heating block mass to resistexcessive temperature changes, or by any combination of these or othertechniques. Additionally, the mass and shape of the heating block may bechosen to ensure that the temperature remains generally uniform and isnot unacceptably perturbed when samples are inserted into or removedfrom the block. The design of suitable incubators (of the heating blocktype or other types) for the first incubation station 232 is well knownin the art, and may be determined mathematically or through routinetesting. If desired, a safety cut-off may be provided to cut power tothe heating element if the temperature rises above a predeterminedlevel, such as about 85 degrees Centigrade. Of course, higher or lowersafety cut-off temperatures could be chosen depending on the particularapplication. For example, if a higher set temperature is used, acorrespondingly higher safety cutoff temperature may be required;alternatively, a lower safety cutoff temperature may be desirable wherevolatile solvents or solvents with a particularly low flash point areused.

In step 322, the ETU is moved to the first aspiration station 238. Thefirst aspiration station 238 comprises a magnet station that is adaptedto hold the ETU and has one or more magnets that are positioned next tothe ETU test tubes. Suitable magnet stations are known in the art. Themagnets may be fixed in place or moved into position when the ETU is inplace, and may comprise any suitable kind of magnet or electromagnet.Such magnets are known in the art, and embodiments of magnetarrangements are described subsequently herein with respect to FIGS. 14Aand 14B. The magnets attract paramagnetic macroscopic beads mixed intothe sample as the first reagent (see above), and capture these beads andany attracted material in place adjacent a sidewall of the tube. In anexemplary embodiment, a horizontal bar may be located opposite themagnets and slightly above them to cause a slight interference with theETU test tubes that presses them against the magnets. Minimizing thedistance between the ETU test tubes and the magnets in this way mayprovide a stronger and more consistent application of the magnetic fieldto the beads, and increase the speed and effectiveness of magnetic beadattraction. While the beads are magnetically captured, one or moreaspirators are lowered into the tubes to remove fluids. Any suitableaspirator, such as known in the art or described subsequently hereinwith reference to FIGS. 15A and 15B, may be used to aspirate the fluidfrom the ETU test tubes. In an exemplary embodiment, the aspirator tipsare made of a nonmagnetic material to avoid magnetic attraction of theaspirator tips to the side of the tube. In the exemplary embodiment, themagnets are applied to the ETU tubes for 90 seconds, and then theaspirator is activated to remove the fluid to a liquid waste receptacle250. The magnets remain applied during aspiration, and preferably aresimply fixed in place and applied at all times. An ultrasonic sensor maybe used to verify that all of the liquid has been removed from the ETUtest tubes after aspiration is complete; such devices are known in theart. The ETU remains in the first aspiration station for one full clockcycle (less time necessary for transport). After aspiration, themagnetic beads and the cells that are being tested remain in the ETUtest tubes, possibly along with some small amount of fluid that was notremoved during aspiration.

After aspirating the ETU test tubes in step 322, the aspirator may becleaned (or the tips may be replaced) to prevent carryover from onesample to the next. Washing may be accomplished by lowering theaspirator into a bath 254 containing water and/or other cleaningsolutions (e.g., bleach followed by water), and aspirating a quantity ofwater. Washing may be done during the initial 90-second magnetapplication in step 322, and preferably does not take a full clock cycleto complete. It is believed that this washing technique is sufficient toprevent sample carryover in the context of an exemplary HPV nucleic acidassay. Optionally, the aspirator may be cleaned by dipping it in and outof a wash solution while vacuum is applied, creating greater turbulenceand shear force due to the intermittent drawing of air, which isexpected to provide greater cleaning ability. The foregoing protocol mayalso attain sufficient cleaning with less production of liquid waste. Ifdesired, testing may be routinely performed to ensure that washing issufficient to achieve acceptably low levels of sample carry-over. Ifgreater cleaning is desired, detergents, organic solvents, salts, and/orheating of the cleaning solution may be employed. The bath 254 also mayuse a continuously or intermittently flowing cleaning solution or watersupply to prevent the accumulation of contaminants therein.

In step 324, the ETU is moved to the second mixing station 236. Like thefirst mixing station 230, the second mixing station may have twosubstations 236 a, 236 b that are mounted on a common platform with acommon shaking mechanism. For step 324, the ETU is placed in the firstsubstation 236 a, and a suitable amount of a second buffer is dispensedinto the ETU test tubes (1000 ul for both protocols) by anotherdispensing unit 252. This dispensing unit may be constructed asdescribed above or in any other suitable way, as known in the art. Afterthe buffer is dispensed, the ETU is mixed (e.g., for 30 seconds at 1500rpm). The ETU remains in the first substation 236 a of the second mixingstation 236 for one full clock cycle (less time necessary fortransport).

Next, in step 326, the ETU is moved to the second aspiration station240, where a magnet is used to attract the paramagnetic beads for 120seconds, and the fluid is aspirated to waste using an aspirator. Theaspirator may be the same aspirator used in step 322, and the aspiratormay be cleaned, such as described above, immediately after thisaspiration step. The use of a 120 second magnet application beforeaspirating in this step may allow more complete capture of the magneticbeads, and may help provide sufficient time for the aspirator to be usedin step 322, cleaned, and then used in step 326 on an ETU that isfurther along in the process path. The ETU remains in the secondaspiration station for one full clock cycle (less time necessary fortransport). If there is insufficient time to perform the both aspirationsteps (i.e., step 322 and 326) one or both of the aspiration stationsmay include a second substation in which a second ETU can be placed.This allows the aspiration in step 326 to overlap clock cycles or occurat the beginning of a second clock cycle.

In step 328, the ETU is moved to the second substation 236 b of thesecond mixing station 236. Here, a suitable amount of a third buffer isdispensed into the ETU test tubes (30 ul for both protocols), and thecontents of the ETU test tubes are once again mixed (e.g., for 30seconds at 1500 rpm). The ETU remains in the second substation 236 b forone full clock cycle (less time necessary for transport).

The ETUs next are conveyed to the second incubation station 234, where,in step 330, the samples are incubated for a suitable time (e.g., 10minutes at 68.5 degrees Centigrade for both protocols). The secondincubation station may comprise any incubator, as known in the art. Asshown in FIG. 2, the second incubation station 234 may include multiplecells, each of which can hold an ETU. Additional or fewer cells may beprovided, as necessary.

After the second incubation is complete, the samples are moved to thefinal transfer station 242 where the samples are transferred to a sampletray 208 in step 332. Here, the ETUs are placed in mounts that hold themin place and magnets are once again applied to the sides of the ETU testtubes to attract and capture the paramagnetic macroscopic beads. Themagnets may be applied, for example, for 120 seconds before the samples(which in this case may comprise concentrated nucleic acid) areaspirated from the ETU test tubes and transferred to respective wellsin, for example, a 96-well sample plate 208. In another embodiment,which uses a 120-second clock cycle, the magnets may be applied forabout 50 seconds. Complete sample transfer may be verified by ultrasonicmeasurement of the liquid level in the plate, as known in the art.Additional reagents or substances, such 20 ul of buffer solution and 45ul of oil, may be added to each well in addition to each sample. Oncethe sample plate 208 is full, it is conveyed to the sample plate output118 for eventual removal.

Any suitable device may be used to transfer the samples to the sampleplate 208. For example one or more pipettors may be used to accomplishthe final transfer of step 332. Examples of such devices are known inthe art. In a preferred embodiment, however, a four-channel, fixed widthpipettor may be used to aspirate samples from the eight ETU test tubesinto a row of eight wells on a standard 96-well plate. This embodimentis described in more detail with reference to FIGS. 16-17B. Using thisdevice, the pipettor secures new disposable pipette tips, aspiratessamples from four adjacent ETU test tubes, dispense the samples intoevery other well along a row of a standard 96-well plate, then ejectsthe used pipette tips into the emptied ETU tubes. The pipettor repeatsthis operation for the remaining four ETU test tubes to fill all eightwells on the sample plate 208. This entire two-part operation iscompleted to fully process an ETU once every clock cycle. To providesome flexibility in when this process starts and stops, the finaltransfer station 242 may have multiple substations that each hold anETU. This permits the final transfer step 332 to start and stop betweensystem clock cycles.

The used pipettes and ETUs are transferred to a solid waste container214. Ejecting the pipettes into the ETU test tubes decreases solid wastevolume, and allows the system to operate for a greater intervals beforeemptying the solid waste output 214.

In the context of certain assays, the foregoing exemplary process andsystem is expected to permit sample throughput of up to about 1,400patient samples per day, providing uncapping, a ten-step samplepreparation process (beginning with the sample adequacy step), andoutput of purified DNA in a convenient 96-well format that can beprocessed in existing analytical equipment. The first group of samples(i.e., the first ETU full of samples) is processed about 50 minutesafter starting the system, with additional ETUs completed in 2.5 minuteintervals thereafter. Consequently, the first 96-well output plate isproduced in about 77.5 minutes, with 30 minute intervals to completesubsequent plates. In other embodiments, the expected throughput of thesystem may be about 35 minutes to the completion of the first ETU withsubsequent ETUs completed at about 2 minute intervals. This results in atime to complete the first 96-well plate is about 57 minutes and withevery subsequent plate taking about 24 minutes to complete afterwards.Of course, the interval time and throughput rate will vary in otherembodiments, depending on the number of processing steps, the sampleprocessing volume (i.e., number of samples being processed at any giventime), and so on.

It will be understood from the foregoing example that embodiments mayprovide a significant benefit by being adapted to perform multipledifferent assay protocols on samples. A random mix of such samples mayeven be provided on a single sample rack. During processing, the sampletype may be identified by recognizing an identifying a characteristic ofthe sample container, reading an indicating feature on a barcode, or byother means. Alternatively, the type of samples on a rack may be mappedand associated with a barcode on the rack that is read when it is placedin the system, or a user may simply manually enter the sample types intothe system. Regardless of the means for identifying the sample type, thesystem may be set up and programmed to process different types ofsamples according to different protocols, such as described aboveregarding the PC and Surepath protocols. As such, mixed groups ofPreservCyt and SurePath samples can be simultaneously accommodated evenin the same ETU. The system can automatically track which type of sampleis in which position and can seamlessly accommodate the protocoldifferences (e.g., differences in quantity or type of reagent added). Inthe foregoing example, the clock cycle accommodates both protocols, andin other embodiments the clock cycle and processing steps can bemodified to accommodate various protocols.

While the foregoing example requires little additional processing forthe two protocols, in other embodiments, additional reagents andprocessing stations may be provided, if necessary, to provide therequired disparate processing steps. In still other embodiments, it maybe possible to modify the processing protocols of two different sampletypes to minimize or eliminate any disparate processing steps. Forexample, it may be possible to use a more similar or even identicalprotocols for PC and Surepath test samples, such as by pre-treatingsamples of one or both types at an early processing stage (e.g., byadding buffer to provide uniform processing volumes). Other variationswill be apparent in view of the present disclosure. It will also beapparent that the nature of the particular reagents, buffers, testsamples, and the like, will vary depending on the desired use of theparticular embodiment, and the details of any particular protocol soughtto be followed during processing. As such, an understanding of the exactnature of particular materials that may be used in exemplary embodimentsis not believed to be necessary to facilitate or illuminate theunderstanding of the invention, and it is not necessary in thisdescription to specifically identify such elements.

Exemplary Embodiments of Processing Equipment and Related Methods

As suggested above, it will be appreciated that any suitable machineryor equipment may be used to move the samples through the PAS 100 and itsvarious processing steps. For example, the systems employed herein canuse a variety of robotics known in the art to automate the movement ofsamples, reagents, and other system components. Exemplary roboticsystems have capabilities to move samples on one, two, or three axesand/or to rotate samples about one, two, or three axes. Exemplaryrobotics move on a track which may be situated above, below, or besidethe workpieces. Typically a robotic component includes a functionalcomponent, e.g., an arm able to grip and/or move a workpiece, insert apipettor, dispense a reagent, aspirate, etc. Robotics may be translatedon a track, e.g., on the top, bottom, or side of a work area, and/or mayinclude articulating segments which allow the arm to reach differentlocations in the work area. Robotics may be driven by motors known inthe art, which may be, for example electrically, pneumatically, orhydraulically powered. Any suitable drive control system may be used tocontrol the robotics, such as standard PLC programming or other methodsknown in the art. Optionally the robotics include position feedbacksystems that optically or mechanically measure position and/or force,and allow the robot to be guided to a desired location. Optionallyrobotics also include position assurance mechanisms, such as mechanicalstops, optical markers or laser guides, that allow particular positionsto be repeatedly obtained.

In view of the present disclosure, the design of suitable embodiments iswithin the skills of the person of ordinary skill in the art withoutundue experimentation. Nevertheless, it has been found that varioussubsystems having particular designs may be used at various locationswithin the PAS 100 or other processing systems to provide suitable orimproved operation. Examples of such systems are described below.

Exemplary Intake and Initial Transfer Equipment

FIG. 4 provides an isometric partial view of the sample intake andinitial transfer area of the embodiment of FIG. 1. Here, it can be seenthat the sample rack input 102 leads to a laterally-traversing track 402upon which the sample racks 201 travel to the barcode reader 218, mixers220 and decapper/capper unit 222. The sample rack 201 that is advancedfurthest along the track 402 may be positioned on an elevator, such as aservo-operated counterweighted platform. Once all of the samples on thesample rack 201 have been processed, the elevator lowers the sample rack201 to a lower laterally-traversing track 414 which conveys the sampleracks 201 to the sample rack output 104. Any suitable conveyor, such aspowered rollers, endless belts, robotic shuttle arms, and so on, may beused to move the racks 201 along the tracks 402, 414.

Two control sample racks 244 and two reject vial racks 246 are installedat the control vial and reject vial access point 106 located at thefront of the device. These racks 244, 246 are mounted on correspondingtracks within the PAS 100. Suitable racks and tracks for this purposeare known in the art and need not be described here.

Referring to FIG. 5, the sample racks 201 may comprise any suitable rackhaving any number of sample holders 502. Each sample holder 502 may beadapted to hold sample bottles 504 of various different sizes. Forexample, each holder 502 may have a relatively small diameter at itslower end 506 that is adapted to hold smaller bottles 504, and arelatively large diameter at its upper end 508 to hold larger bottles(not shown). A depressed area or opening 510 may be provided at thebottom of the holder 502 to help center and hold bottles 504 having apointed, rounded or conical end 512, such as the shown bottle 504.

Referring back to FIG. 4, an access arm 404 is pivotally and verticallymounted on a shuttle 406 that, in turn, is adapted to move laterallyalong an access arm track 408 located above the sample racks 201. Byselectively rotating the access arm 404 about the shuttle 406, raisingand lowering the access arm 404, and traversing the shuttle along thetrack 408, the access arm 404 can access to the all of the sampleslocated on the sample rack 201 nearest the barcode reader 218. Inaddition, to provide continuous operation when the elevator is movingthe racks down to the lower track for removal, the access arm 404 may befurther adapted to access at least some of the samples located on thenext sample rack 201. Any suitable drive mechanisms and control systemsmay be used to manipulate the access arm 404, and such devices are wellknown in the art and need not be described here. The access arm 404 mayalternatively be replaced by a multi-pivot robotic arm the can accessall of the necessary sample rack locations without requiring a movingshuttle. In other embodiments, the racks 201 may be moved to assist theaccess arm with picking up and depositing sample bottles 412. Othervariations on an access arm 404 or other kinds of transfer mechanismsmay be used in other embodiments.

At its distal end, the access arm 404 has a gripper 410 that is adaptedto grasp and move sample bottles 412 having various sizes. The gripperincludes a contact surface that transmits force to the sample bottle tocontrol its positioning and movement. The gripper may include multipleelements that apply differential forces to the sample bottle. Forexample, one element may hold the bottle body, and another may hold thebottle's lid and apply a force to remove it. Many different grippers arewell known in the art and may be used within the spirit and scope of thepresent disclosure; accordingly the following descriptions of exemplarygrippers should be understood to be illustrative, rather than limiting.In the shown example, the gripper 410 may comprise an expandable chuckor finger-style having a jaws that accommodate generally circular samplebottles 412. The jaws may be stepped to grasp bottles having differentdiameters at each step location. One or more of the jaws may be moveablesuch as by being pneumatically actuated, hydraulically actuated, drivenby a motor, or being coupled to a spring or a flexible material. Themovement may be translational and/or pivoting. An example of anothersuitable gripper is provided in U.S. Patent Publication No.2008/0247914, which is incorporated herein by reference.

Other suitable grippers maybe used as well. For example, a bellowsgripper may be used, or a strap gripper may be used (i.e., a grippershaving a flexible material, such as metal, leather, rubber, plastic,etc., forming a loop that is tightened around a workpiece). A suctioncup gripper may be used as well. Suction cup grippers have a contactsurface able to form an air-tight seal against a workpiece, allowing theworkpiece to be held by a vacuum. A vacuum seal may be formed byevacuating air (using a pump or by pressing the suction cup against theworkpiece) out of a chamber defined by the workpiece surface and thegripper surface. Alternatively, or in addition, the volume of thechamber may be increased by applying a force that pulls the grippersurface, also resulting in partial vacuum. Once a partial vacuum isestablished, the workpiece is held against the gripper by atmosphericpressure. The workpiece may then be released by restoring ambientpressure within the chamber, which breaks the seal, such as by openingof a passage through the gripper, deformation of the contact surfacebetween the gripper and workpiece, or allowing air or another fluid topass out of or through the workpiece into the chamber. A magneticgripper also may be used. Magnetic grippers include a magnetized portionable to apply force to a workpiece. The magnetic force may becontrollably released, for example by use of an electromagnet that isturned on and off, and/or by having a magnetized portion that is able tomove relative to a contact surface, such that the magnetized portion canbe moved away from a workpiece to facilitate release. Alternatively, amagnetic gripper may release a workpiece by having the workpiece grabbedby another gripper, whereby the workpiece is released when the magneticgripper is withdrawn.

The access arm 404 is programmed to remove each sample bottle 412 fromthe sample rack 201, place the bottle 412 in the barcode reader 218,remove the bottle 412 from the barcode reader 218 after a sample istaken, and return the bottle 412 to the location on the rack 201 fromwhich it was taken. In addition, the access arm 404 may be adapted toremove control samples from the control sample racks 244, and placerejected samples on the reject vial racks 246.

Exemplary DCU Equipment

FIGS. 6A and 6B illustrate an exemplary barcode reader 218, shaker unit220 and decapper/capper unit 222 in greater detail. Collectively, theseare referred to herein as the “DCU,” but a DCU may also comprise onlysome of these elements and/or other elements. The DCU may be usedaccording to the processes described herein, or in other ways, toprovide high volume processing of specimens in various contexts and toreduce the need to rely on labor intensive processes that may subjectpersonnel to exposure to samples and repetitive motion injuries. Forexample, the DCU may be used as an open platform system that can beintegrated into various processing systems, or used as a separateself-contained unit. Various applications exist for a DCU such as theones described herein, and particular application may be found in liquidcytology processes, such processing cervical specimens, PAP smeartesting, HPV DNA testing, and so on.

In the exemplary embodiment, a barcode reader 218 may comprise acylindrical chamber 602 into which an access arm or other device insertsa sample bottle 604. The chamber 602 may be adapted to hold variousdifferent types of sample bottles 604, such as discussed elsewhereherein. One or more barcode scanners 606 are provided around theperiphery of the barcode reader 218. the chamber 602 may be adapted torotate to bring a barcode on the bottle 604 into view of one or bothscanners 606 to read the code. In other embodiments, a transport arm 608may be used to hold and rotate the bottle 604. The transport arm 608 maycomprise any suitable gripper and drive mechanisms, and may be adaptedto convey the bottle 604 to the shaker unit 220 and/or decapper/capperunit 222. An example of a suitable transport arm gripper is shown inFIG. 7B, which illustrates a chuck 720 having two jaws 722 mounted toit. The chuck 720 is mounted on a spindle and driven by a suitable motorto rotate it. The jaws 722 are adapted to move radially in an outrelative to the rotating axis of the chuck 720 in order to grip thebottles 724, 726, although in other embodiments other gripping movementsmay be used, as known in the art. As shown in the two illustrations, atleast two different size bottles 724, 726 may be manipulated by thechuck 720. This may be facilitated by providing the jaws 722 with steps728, 730 that correspond to different bottle sizes, such as shown. Inother embodiments, different bottle sizes may be accommodated byproviding the jaws 722 with a large range of travel, or by other means.While the shown barcode reader 218 may be suitable in some embodiments,it will be appreciated that it may be moved or replaced by a barcodereader mounted on an access arm that loads samples directly into theshaker unit 220 or decapper/capper unit 222. A reader also may be placedin other locations, such as described elsewhere herein.

The shaker unit 220 may comprise any suitable arrangement of one or moresample mixers. Such devices are typically operated by an offset drivesystem or other mechanism, and are generally well-known in the art. Inthe shown embodiment, two shakers are provided in the shaker unit 220.Each shaker comprises a pair of adjacent cylindrical chambers 610, 612,each of which is adapted to hold bottles having one or more differentsizes. In one embodiment, shown in FIG. 7C, the a pair of shakers 702may be mounted on a platform 704 that is adapted to move along a track706 before, after or during the shaking operation. These shakers 702 mayinclude multiple joined chambers for holding different size bottles. Inaddition, an idle holding chamber 708 that does not shake, but isassociated with the DCU and used to hold one or more sample bottles atintermediate transport stages may be provided on the platform 704 orelsewhere in this or other embodiments.

The decapper/capper unit 222 is located adjacent the shaker unit 220.The exemplary decapper/capper unit 222 comprises two bottle grips 614that are adapted to hold the bottoms of the sample bottles 604(preferably regardless of the size or shape), and two cap grips 616 thatare adapted to grip and turn the bottles' caps. The bottle grips 614 maybe mounted on a rotating platform 618, the purpose of which is describedbelow. Referring to FIG. 7A, and exemplary bottle grip 614 may comprisea bellows grip. The bellows grippers are pneumatically or hydraulicallyactuated devices that have an inflatable bladder 712 that can beinflated to press into contact with the bottle 604. The bladder 712 isshaped generally like a cylinder, torus, or elongated torus, and islocated inside a rigid cylinder 716 against which it presses to generatea griping force when it is inflated. In other embodiments, the bladder712 may have other shapes, and may operate by pressing the bottle 604against a stationary surface or by other means. The bladder 712 may bemade of any material able to expand when the actuating substance ispressurized, such as rubber, plastic, or other elastomeric material. Thebladder's surface may be used to contact and grip the bottle 604.

In the shown exemplary embodiment, a number of ribs 714 are disposed atvarious locations around the inner circumference of the bladder 712 andsecured to the bladder 712 by adhesives, stitches, or other means. Theribs 714 are believed to help orient the bottle 604 in an uprightorientation, and may improve grip on the bottle 604. The ribs 714 mayhelp grip different size bottles, but it also may be desirable in otherembodiments to remove the ribs to possibly facilitate a larger range ofbottle sizes. The ribs 714 may be smooth rods, or they may be treated toincrease their frictional contact with the bottle. Even with the ribs714 present, some of the bladder's surface may still contact the bottle604 when the bladder is inflated. The bladder 712 may include otherfeatures in other embodiments. For example, the bladder 712 may havecircumferential steps to help center and hold different size samplebottles 604. While the foregoing bellows grips 614 may be preferred insome embodiments, other grips, such as expanding chucks or jaws, strapgrips, and the like, may be used in other embodiments.

As noted above, the decapper/capper unit 222 also includes a pair of capgrips 616. The cap grips may comprise any suitable mechanism having agrip to hold the appropriate size bottle caps, and a drive mechanism torotate the grip. The cap grips 616 also may have a vertical movementcomponent to raise them and lower them as needed to grasp and remove thebottle caps. An embodiment of such a grip is discussed above withrespect to FIG. 7B. Of course, other designs may be used in otherembodiments, such as those described elsewhere herein or as known in theart. For example, the embodiments of FIGS. 6A and 6B are similar to thatshown in FIG. 7B, but may use three stepped jaws 620 instead of two. Thecap grips 616 may be mounted on a traversing arm or a rack so that theycan be moved laterally. In such an embodiment, the cap grips 616 may beused to pick up bottles from the shaker unit 220 and move them to thebottle grips 614.

In use, a transfer mechanism, which may be the transport arm 608 used torotate the bottles in the barcode reader 218 or some other mechanism,such as the cap grips 616, conveys bottles to the bottle grips 614 andlowers them into place. The bellows in the bottle grips 614 preferablyare inflated before the transfer mechanism lets go of the bottle 604, tothereby expand the bladder 712 and securely hold the bottle 604 centeredin the bellows. This centering action helps ensure that the bottles arecentered and that the cap grips 616 will be able to effectively graspthe bottle caps. The bellows is kept inflated to ensure that properalignment is retained during subsequent steps and until recapping iscompleted. Each bellows 614 preferably may be independently inflated,but this is not strictly necessary.

During uncapping, the bottle grip 614 holds the bottom of the bottle604, and the cap grip 616 holds the bottle cap. The cap grip 616 isrotated and uncapping can be detected by measuring displacement as afunction of time, with a screw cap being fully unscrewed when thedisplacement no longer increases with further rotation. At this pointthe cap gripper 616 may be actively raised to clear the rest of thebottle 604. Uncapping can also be performed by applying an upward forcethat immediately separates the base and cap once the threads are nolonger engaged. Screw caps on cervical sample bottles such as those usedon standard SurePath or PreservCyt® vials can be uncapped using these orother methods. Where the cap grip 616 must accommodate caps of differentsizes and bottles of different lengths, the cap grip 616 may becontrolled in any suitable way. In one embodiment, in which two bottlesare addressed, with one being taller and narrower and the other beingshorter and wider, the difference in shape can be accounted for simplyby making the cap grip 616 jaws stepped to hold the tall, narrow bottleat an upper location, and the wide, short bottle at a lower location.the embodiment of FIGS. 6A and 6B may provide this functionality.

Recapping is accomplished essentially by reversing the steps ofuncapping. Preferably the base of the opening of the cap is slightlywider than the top of the bottle such that alignment is simplified.Alignment of the base and cap may be assisted or accomplished by sensors(e.g., optical or ultrasonic sensors that directly or indirectlydetermine the position of the base or cap) or by controlling thepositions of the grips 614, 616 using accurate motion control mechanismssuch as stepper motors or servos.

While the shown embodiments generally refer to decapping and cappingoperations for threaded twist-off caps, it will be understood that, inother embodiments, the DCU may be adapted to perform these operations onpushcaps instead of or in addition to threaded caps. In such anembodiment, the grips 614, 616 may be adapted to apply a force to pullthe cap off a bottle. Such modifications should be apparent based on thepresent disclosure. Exemplary embodiments of such pushcaps are found,for example, in U.S. application Ser. No. ______, entitled “Closure andMethod of Using Same” and filed on Oct. 9, 2009 (also identified asAttorney Docket No. 74708.000101), which is incorporated herein byreference in its entirety.

As noted above, the decapper/capper unit 222 may be mounted on arotating platform 618. The platform 618 may be rotated as needed by anysuitable drive mechanism and control system. As explained in more detailin the below exemplary process examples, the platform 618 may be rotatedto positioned the bottles contained in the bottle grips 614 at variouslocations for various processing steps. For example, the platform may berotated 90 degrees to locate a bottle at a pipetting station where anpipette is used to aspirate a sample from the bottle. Thedecapper/capper unit 222 is shown in the decapping (andcapping)-position in FIG. 6A, and in the aspirating position in FIG. 6B.

To avoid crashing the pipette tip into the bottom of a tube, aspirationmay take place with a pipette at some distance from the bottom of atube. Samples may be provided in a flat-bottom bottle or tube or Otherconfiguration from which it is difficult to automatically pipette theentire sample, resulting in a high dead volume. In an exemplaryembodiment, the input sample bottle 604 may be tilted (for example, heldat an angle between about 15 and 20 degrees from vertical) duringpipetting, such that dead volume is reduced by causing the sample tocollect at the lowered part of the tube. For example, pipetting may beperformed with the pipette tip approximately 1 millimeter from thebottom of a standard PreservCyt vial, resulting in approximately 1 mL ofdead volume due to the flat tube bottom. By tipping the vial, the sameapproximately 1 mm separation between pipette tip and the bottom of thetube results in a dead volume of only approximately 0.1 mL. Thus,tipping allows approximately 0.9 mL of additional sample volume to berecovered. As the required assay volume typically is only a fewmilliliters (depending on the particular assay performed), increasedrecovery of an additional 0.9 mL can greatly decrease the fraction ofsamples that might otherwise be rejected (or require manualintervention) due to insufficient volume.

Tipping can be accomplished by standard methods known in the art. In theshown embodiment, the bottle grips 614 are mounted on hinged portions ofthe rotating platform 618. Pneumatic linkages 622 are connected toplatform 618, and adapted to raise the platform 618 at the pipettingstation, such as shown in FIG. 6B. When tilting is not required, thehinged portions of the platform may be held in a horizontal position bethe linkages 622 or simply by gravity. Just prior to pipetting, thepneumatic linkage is activated to tilt the platform 618, grip 614, andbottle 604.

The decapper/capper unit 222 may be provided with other features andfunctions. For example, a process flow may be used to ensure that onlyone input sample container is opened at any given time to minimize therisk of cross-contamination or of inadvertent mis-placement of a cap ona different input sample container than its original input samplecontainer. Also, the pipette that aspirates the sample from the bottle604 may be adapted to add an additional reagent to the bottle. Anexample of such a pipette is shown in FIG. 7D. Here, a standard pipettor(e.g., a 5 ml pipettor) has been modified to include an integral reagentdispensing pump 734 (e.g., a Z-series pump available from TricontinentScientific, Inc. or Grass Valley, Calif.). A pneumatic cylinder 736 isalso provided to eject used pipette tips 738.

Exemplary Open Platform DCU (“DCU-OP”)

As noted above, in one embodiment, a DCU may be provided in anopen-platform format. For ease of reference, an open platform DCU isreferred to herein as a “DCU-OP.” A DCU-OP may be desirable, forexample, where it is desired to pre-process a large number of samplesfor later testing, but the pre-processing steps generally do not includeintensive sample processing steps such as incubation and multipleaspirations. A DCU-OP also may be desirable, even in relativelylow-volume applications, where it is desired to avoid direct exposure toa sample or to reduce ergonomic hazards such as repetitive stressdisorders.

A DCU-OP may be controlled as described above with respect to the PAS100, or using any other suitable means. In one embodiment, a DCU-OP maybe controlled by a computer running software and having a graphical userinterface, touch screen, keyboard, barcode scanner, mouse, or otherfeatures. Data may be transferred between the DCU and the computer orother devices by any suitable means, such as flash drives, directconnection, wireless connection, and so on.

A DCU-OP preferably may be operated continuously or as a batch modedevice. Samples and materials may be provided to the DCU-OP usingmechanisms like those described above (e.g., sample rack, ETU rack,access arm, etc.), but other systems, including manual operation, mayused in other embodiments. Output may be to ETUs or other sample racks.Examples of standard output racks (which also may be used in otherembodiments described herein) include QIAsymphony racks and MST vortexerracks. A specific rack also may be developed for the DCU-OP system, orthe system may be adapted to use any suitable generic rack.

A DCU-OP may be operated in any suitable way. For example, in oneembodiment, a DCU-OP may be operated by powering on the machine,selecting the appropriate output tube type from a list of supported tubetypes, and selecting an output rack type from a list of supported outputrack types. In order to provide broad open platform capabilities, thesystem may include an extensive library of suitable input and outputsample formats. The DCU-OP input and rack handling system may be adaptedto handle sample holding racks that hold numerous sample formats (e.g.,cervical sample tubes, urine tubes, blood tubes, etc.), as well asadditional alternative racks to hold other formats. To provide evengreater flexibility, the DCU-OP may be programmed to permit a user toenter input tube, input rack, or output rack dimensions, such as height,diameter, width, length, sample spacing, well locations and dimensions,and so on, and the machine may use this input to calculate appropriatealgorithms for finding and manipulating samples.

The operator may create matching barcodes for input and output tubes,and then label the tubes. The input tubes or samples may then be scannedand placed in a rack in an order specified by the software (the rackalso may be specified by the software), so that the software has anaccurate map of the rack contents. The output tubes also may be scannedand placed in a rack in an order specified by the software. These stepsmay help ensure that the software has an accurate map of the rackcontents. The loaded racks may then be placed in the DCU-OP, along withany necessary reagents and consumables, such as pipette tips. Before arun begins, the operator also may empty the solid and liquid wastercontainers. The operator also may enter values for reagent depositionvolumes, mixing times, sample volumes, and so on. After preparations arecomplete, the operator initiates a processing run, and may monitor therun, review the run report, and edit, save and print the report asnecessary. The report also may be automatically saved and transmitted toother processing stations, such as a sample analyzer into which theprocesses samples are eventually loaded or a central control unit thatcommunicates with the DCU-OP and the analyzer.

During the run, the DCU-OP may use a PLC controller or other controllogic to select and use sensors that monitor some or all of theprocessing steps to assure quality control and correct handling of thesamples. Any suitable barcode or other sensor may be used to assist withthis monitoring. Anomalies in the workflow or scans may be reported andtraced as well. These features are of particular interest in clinicalmarkets, in which control and monitoring of samples assures correctdiagnosis or health status reporting of patients.

FIG. 26 illustrates an exemplary embodiment of a DCU-OP 2600. Here, theDCU-OP includes two loading racks 2602, 2604. The left rack 2602 holdspipette tips 2606 and output trays 2608, reagent bottles 2610, and asolid and liquid waste containers 2612. The right tray 2604 holds sampleracks 2614, each of which holds a number of bottles 2616 (e.g.,Preservcyt™ sample bottles available from Hologic, Inc of BedfordMass.). The trays 2602, 2604 are slid into place in the DCU-OP housing2618 for operation. An associated computer 2620 may be provided adjacentto the housing 2618. Preferably, the racks 2602, 2604 are configured toallow manual scanning operations to occur as the various components areloaded in them, and they may be arranged to be at about the same heightas a standard lab bench or cart to assist with scanning and loading. Ifdesired, the entire DCU-OP may be mounted on wheels to be movable.

While the DCU-OP may output samples to ETUs or sample plates such as96-well plates, it also may be adapted to output samples to individualtest tubes. Examples of output tubes include: 15 mL vials having conicalbottoms, threaded tops, a diameter of 17 mm and a length of 118 mm; 10mL vials having round internal bottom ends, threaded tops, a diameter of16 mm and a length of 79 mm; 14 mL vials having round bottom ends,flanged tops, a diameter of 17 mm and a length of 100 mm; 10 mL vialshaving round bottom ends, unthreaded tops, a diameter of 16 mm and alength of 100 mm; 9 mL vials having round bottom ends, unthreaded tops,a diameter of 13 mm and a length of 100 mm; and 4 mL vials having roundbottom ends, threaded tops, a diameter of 15 mm and a length of 75 mm.Preferably, a DCU-OP can be configured to process all of these differentoutput vial types, and may be able to process more than one output vialtype in a single operation run. Of course, embodiments of other systemsdescribed herein, such as the PAS 100, also may output to individualtubes such as those describe above or constructed otherwise.

During operation, the DCU-OP may perform any of the processes describedherein, and may perform other processes as well.

Exemplary DCU Process Flow

FIG. 8 illustrates a process flow for extracting and processing a samplecontainer. This process may be used by the DCUs or DCU-OPs describedabove or other systems. In this exemplary embodiment, the sample isaccessed and transferring the sample to an output container. Manyvariations and arrangements of the process may be made. For example, asample adequacy determination may be made using techniques known in theart or described or referenced elsewhere herein. Although FIG. 8 depictsa process flow for a single sample container it should be understoodthat in some embodiments, different sample containers may be processedconcurrently. In these embodiments, one or more secondary samplecontainers may be processed during the processing of a first sample.Redundant components or components with capacity to handle a pluralityof samples may be used to facilitate concurrent processing of samplesand to increase sample processing throughput. For example, a mixingstation may contain a plurality of mixers which may allow a plurality ofsamples to be mixed concurrently. An uncapping and recapping station mayalso contain a plurality of grippers and uncappers. Processes thathandle multiple samples concurrently may take one or more precautions toprevent sample contamination. For example, the system may be operatedsuch that only one sample is uncapped at any time. Furthermore, a capfrom a sample container may not be released from the sample container orotherwise put in contact with a surface other than the correspondingsample container.

Returning to the exemplary process of FIG. 8, the process may begin atstep 802. At step 802, a sample container may be pulled from an inputrack by and transfer arm having a gripper adapted to hold the samplecontainer. The transfer arm may be capable of moving on one, two, orthree axes, and may be operated by any suitable electric, hydraulic,pneumatic or other actuators. Components of an transfer arm may providefurther positioning and sample manipulation capabilities (e.g., agripper may be capable of rotating or tilting a sample). An input rackmay be of one or more standard sizes, and may hold samples of varioussizes.

The size of an input rack and the size and coordinates of one or moresample containers associated with the rack may be known or determined bya processor communicatively coupled to the transfer arm, as known in theart. According to some embodiments, the transfer arm may containadditional sensors to facilitate positioning of an the gripper toretrieve the sample container. Such sensors may include, but are notlimited to, optical sensors, ultrasonic sensors, and pressure sensors.Position assurance systems such as, for example, mechanical stops, mayalso be used. Once the transfer arm is located over a desired sample,the gripper may be used to retrieve the sample.

At step 804 of the exemplary process, a barcode may be read, an RFID tagmay be detected or other methods may be performed to verify the identityof a retrieved sample container. The transfer arm retrieving the samplecontainer may contain a barcode reader or it may pass the samplecontainer in front of a barcode reader. In such embodiments, the grippermay be configured with a rotating head that can rotate the samplecontainer in front of the barcode reader, wherever it is positioned, tofacilitate barcode scanning. In this way, barcode scanning may beperformed in transit from an input sample rack to a desired location.The barcode reader also may comprise a separate station in which thesample container is placed, such as described above.

At step 806 a sample may be placed in a mixing station. A mixing stationmay contain one or more mechanisms for mixing or agitating a sample(e.g., an orbital mixer). A mixing station may be of a known location sothat a processor communicatively coupled to an transfer arm may providecoordinates to an transfer arm. A mixing station may contain one or moremixers or agitators capable of receiving a sample container. Mixingtimes may be specified by a process communicatively coupled with themixing station or may preset at a component of the mixing station.

According to some embodiments, a mixing or agitating apparatus may beincorporated into an transfer arm so that a sample may be mixed duringtransit. In these embodiments, transfer to a mixing station may not benecessary and a sample may be placed in an uncapping station afterretrieval from an input tray.

At step 808, after completion of mixing, a sample may be transferred toan uncapping station. According to some embodiments, transfer from amixing station may be performed by a second transfer arm which may beseparate from and operate independently of a transfer arm retrievingsamples from an input tray. According to other embodiments, the sametransfer arm may retrieve samples from an input tray and place samplesin an uncapping station.

An uncapping station may contain one or more grippers for receiving,holding, and releasing a sample container. An uncapping station may alsocontain one or more uncappers. An uncapping station may be capable ofrotating a received sample between two or more positions. For example, afirst position may be used for receiving a sample from a transfer arm, asecond position may be located beneath a first uncapper, a thirdposition may be used for pipetting or otherwise accessing a sample, anda fourth position may be located beneath a second uncapper. Afterreceiving a sample from a transfer arm, an uncapping station may rotateor otherwise transport the sample beneath an uncapper.

At step 810, the sample container cap may be removed. After removal ofthe sample cap, the sample may be rotated or otherwise transported to aposition for sample access. The position may be accessible by apipetting arm.

Prior to pipetting one or more additional steps may be performed. Atstep 812, a liquid level in a sample container may be sensed. The liquidlevel in a sample vial is optionally sensed (e.g., with an optical,ultrasonic, or mass-based sensor, or by measuring the liquid volumepipetted from the vial) to determine whether tilting is required toobtain the desired sample volume and/or to ensure that the sample volumeis low enough to permit tilting to a given angle without causing aspill.

At step 814, the sample may be aliquoted by a pipetting arm. Thealiquoted sample may be transferred to an output container (e.g., anopen position on an ETU).

After the sample has been withdrawn, the uncapping station may rotatethe sample under the same uncapper that removed that sample cap. At step816, the sample container may be recapped by essentially reversing thesame steps used for uncapping.

After recapping, the uncapping station may rotate the sample to aposition accessible by a transfer arm for return to the input rack. Atstep 818, the sample may be returned to the input rack.

FIG. 9A provides an overview of an exemplary station that provides inputsample uncapping and transfer to ETUs. The samples are provided in tubesthat are held in a sample rack 902 of any suitable type. A mixingstation 912 is provided having as mixers M1 and M2 that are able to gripa tube and agitate its contents by an orbital platform motion. H1 is aholding station able to grip a tube. G1 and G2 are grippers 926 and 928(for example, bellows grippers) that hold the lower part of a tube foruncapping. The grippers 926 and 928 are mounted to an uncapping station924 that rotates to different positions to permit the sample containedin each gripper to access different functions (sample ingress or egress,uncapping, pipetting). Variant forms of the output rack 936 may employdifferent container formats, such as 15 mL conical tubes, ETUs, 96-wellplates, 384-well plates, etc. Note that the word “output” refers tobeing the output of the uncapping and sample transfer process, and,accordingly, the output may be used as the input of a subsequentautomated processing step.

As illustrated in FIG. 9A, input rack 902 may be accessible by transferarm 904. Transfer arm 904 may contain gripper 906 for retrieving,holding, and releasing sample 908. Transfer arm 904 may retrieve one ormore samples as described in reference to step 802 of FIG. 8. Transferarm 904 may also contain barcode reader 910 for reading a sample barcodein accordance with step 804 of FIG. 8. At step 806 transfer arm 904 mayplace a retrieved sample in either mixer 914 or mixer 918 of mixingstation 912. Mixing station 912 may also contain a holding station H1 ata holding location 916 which may receive, hold, and release samples fromone or more transfer arms. Samples received at mixing station 912 may bemixed in accordance with step 806.

As described above in reference to FIG. 8, in step 808, transfer arm 920may retrieve one or more samples, such as sample 922, from mixingstation 912 for transport to uncapping station 924. Grippers 926 and 928of uncapping station 924 may be accessible by one or more uncappers foruncapping as described in step 810. Uncapping station 924 may alsorotate allowing access to pipetting and dispensing arm 930. Pipettingand dispensing arm 930 may contain one or more sensors for detecting asample level in accordance with step 812 of FIG. 8. Pipetting anddispensing arm 930 may contain pipette 932 for aliquotting from a sampleas described in reference to step 814 of FIG. 8. Pipetting anddispensing arm 930 may contain dispenser 934 for dispensing reagents orother materials into one or more output containers such as for example,a container, or a portion of output rack 936. Dispensing may occur whenall sample containers are capped to reduce a chance of contamination.According to some embodiments, dispensing may occur for a plurality ofcontainers on an output rack after the output rack has been filled.

After withdrawal of a sample has completed, uncapping station 924 mayrotate a sample container back to a position under an uncapper so thatthe container may be recapped. Recapping may occur as described above inreference to step 816 of FIG. 8. After recapping is completed, transferarm 920 may retrieve a sample from the uncapping station and place thesample in holding location 916 of mixing station 912. Transfer arm 904may return the sample to input rack 902.

FIG. 9B shows functions provided by an exemplary uncapping station. FIG.9B illustrates rotation of the grippers to different positions toprovide access of the sample tubes for different functions. FIG. 9Cshows the functions available at each position. Uncapper 1 (U1) andUncapper 2 (U2) are independently activated to uncap or recap a samplevial. A system may be configured to ensure that only one vial isuncapped at a time, which decreases the possibility ofcross-contamination and prevents caps from being replaced on a differentvial than they came from. Transfer arm refers to access for ingress oregress of sample vials. Pipetting arm refers to access of a pipettor,e.g., to draw a volume of the sample out of the sample vial. Optionally,before or during pipetting of the sample out of the sample vial, thevial is tilted at an angle, such as an angle between about 10-20 degreesor about 10-35 degrees, such that sample dead volume is decreased. Theexact tilt angle may vary depending on the particular sample bottle andpipette geometry, and, while these ranges are believed to have aparticular beneficial use in some circumstances, they are meant to beexemplary. The liquid level in a sample vial is optionally sensed (e.g.,with an optical, ultrasonic, or mass-based sensor, or by measuring theliquid volume pipetted from the vial) to determine whether tilting isrequired to obtain the desired sample volume and/or to ensure that thesample volume is low enough to permit tilting to a given angle withoutcausing a spill.

FIGS. 10A-F illustrate an exemplary uncapping and sample transfer workflow. Sample vials are shown with lower-case letters a through f. Systemthroughput is illustrated by subsequent samples moving sequentiallybehind one another through the various stations. The use of station H1for sample holding is optional; for example, the first transfer arm maydirectly reach the transfer position in the uncapping station. Thebarcode reader may be attached to the first transfer arm as depicted, ormay be located in a fixed position; additionally, a separate transferarm may pick up samples for barcode reading. Problems with a particularsample, such as barcode not recognized, sample volume insufficient,sample turbidity insufficient, unable to open cap, etc. may result in asample being returned to its vial (if it already been drawn) and thevial being deposited in a “reject tray” rather than back in its originalposition in the input rack. As illustrated in FIG. 10A, sample a may bemixed in mixer 914 separately and independently from sample b. Sample bmay be mixed concurrently in mixer 918.

As illustrated in FIG. 10B, sample a may be transferred to gripper 926after completion of mixing. This may allow the transfer of sample c frominput rack 902 to mixer 914. As shown in FIG. 10C, uncapping station 924may receive sample a in gripper 926 and rotate sample a beneath uncapper1002. Uncapper 1002 may remove cap a. As shown in FIG. 10D, uncappingstation 924 may be rotated so that sample a may be accessed by pipettingand dispensing arm 930. In this position, gripper 928 may be accessibleto transfer arm 920. Transfer arm 920 may place sample b in gripper 928.After the removal of sample b from mixer 918, transfer arm 904 mayretrieve sample d, scan a barcode of sample d, and place sample d inmixer 918. Mixing of sample d may commence.

As illustrated in FIG. 10E, after completion of sample extraction fromsample a by pipetting and dispensing arm 930 and depositing of sample bin gripper 928, uncapping station 924 may rotate sample a back beneathuncapper 1002. Sample a may be recapped. After recapping, according tosome embodiments, pipetting and dispensing arm 930 may add one or morereagents to sample a in output rack 936. After capping of sample a,uncapper 1004 may uncap sample b. Once sample b is uncapped, uncappingstation 924 may rotate allowing sample a to be retrieved by transfer arm920 and placed in holding location 916 of mixing station 912. Aftersample a is placed in holding location 916, transfer arm 920 mayretrieve sample c from mixer 914.

As shown in FIG. 10F, transfer arm 920 may place sample c in gripper 926of uncapping station 924. Sample b may be accessed concurrently bypipetting and dispensing arm 930 to allow drawing of a sample anddepositing of the sample into output rack 936. Transfer arm 904 mayretrieve sample e, scan a barcode of sample e, and deposit sample e inmixer 914. Mixing of sample e may commence. Transfer arm 904 may returnsample a from holding location 916 to input rack 902.

As with other features, processes and devices described herein theforegoing embodiments of a DCU and its processing steps may be used inother embodiments, and may even be provided as a standalone unit that isused for upstream sample processing.

Exemplary Extraction Tube Units and Grippers

FIG. 11 illustrates and exemplary embodiment of an extraction tube unit(“ETU”) 1100 that may be used as an intermediary vessel in the processesand systems described herein or in other systems. This ETU 1100 may besimilar or identical to the one described above with respect to FIGS. 1and 2. Typically an ETU will include an identifying feature, such as abarcode, and a gripping surface that facilitates holding and/or movementof the ETU by an automated system. An individual sample position or testtube within an ETU may be referred to as an ETU tube or ETU position.

The exemplary ETU 1100 comprises a frame 1102 and a number of test tubes1104. In this embodiment, eight test tubes 1104 are provided, and eachETU corresponds to a column of a typical 96-well sample plate. However,twelve-tube ETUs and ETUs having other numbers of test tubes may be usedin other embodiments. The frame 1102 may comprises a rigid structurethat has suitable strength to convey the tubes 1104 and samplescontained therein throughout the processing steps without substantiallydeforming under applied loads. The material also should be stable andsufficiently strong at the operating temperatures within the system.Suitable materials may include, for example, metal, wood, or plastic(e.g., nylon, polyvinylchloride, polypropylene, polystyrenes such as ABSand HIPS, etc.).

The tubes 1104 may comprise any suitable shape. The embodiment depictedhas a round bottom which facilitates vortex mixing and minimizespipetting dead volume. Conical bottom tubes would also share thesecharacteristics. Other shapes, such as flat-bottomed shapes, may be usedin other embodiments. The tubes 1104 may be configured to facilitateupstream or downstream processing. For example, the distance betweeneach tube 1104 may be about 18 mm, which corresponds to about twice thespace between the wells in a standard 96-well microplate. This spacingpermits a fixed-width 4-channel pipettor to draw samples from 4 tubeswithin the ETU and dispense the samples into alternating positions in a96-well microplate such as described below, which facilitates transferof samples. The tubes 1104 may be made of any suitable material, such asglass or plastic. Where optical testing is conducted, such as in aturbidity test, the test tubes 1104 preferably is formed in part orentirely from a transparent or semi-transparent material havingsufficient clarity and transparency to permit the desired testing. Thetest tubes 1104 may be formed integrally with the frame 1102 (such as byforming them from the same material that forms the frame 1102 or moldingthem in place within the frame 1102), or formed separately and joined tothe frame (such as by press-fitment, adhesives, fasteners, threadsformed on the test tubes 1104, and so on).

The test tubes 1104 are arranged in a line along the length of the frame1102, but in other embodiments, in which the frame 1102 may havedifferent shapes, the test tubes 1104 may be arranged in any othersuitable array or pattern.

As shown in FIG. 11, frame 1102 is elongated, and may have enlarged ends1106 that result in recesses being formed along one or both long sidesof the frame 1102. In the shown embodiment, the frame has a “dog bone”shape as viewed from above. As a result of providing the enlarged ends1106, the recesses create spaces between adjacent ETUs when multipleETUs are tightly packed together. This permits a gripper 1200, describedbelow, to access and individually grasp each ETU 1100. The ETU 1100 alsomay include registration features that help the user properly align theETU in the system. For example, where it is desired for the ETU 1100 tobe placed in the PAS 100 in only one orientation, the frame 1102 mayhave a notch 1118 at one end that helps identify the proper orientation.The notch 1118 or other registration feature may also engage acorresponding feature in the PAS 100 or other equipment to preventinstallation in the incorrect orientation.

The frame may have a horizontal groove 1108 and a vertical groove 1110on each long side. The grooves 1108, 1110 may be formed using anysuitable manufacturing process. In the shown embodiment, the ETU frame1102 is molded from plastic in a 2-part mold. An upper mold half formsthe top of the frame 1102, and a lower mold part forms the bottom of theframe 1102. This arrangement has been found to be favorable in at leastsome embodiments because it permits the frame 1102 to be easily andinexpensively formed with a rigid outer perimeter wall 1112, cylindricalbosses 1114 to support each tube 1104, and one or more cutouts orrecesses 1116 between the perimeter wall 1112 and bosses 1114. Thisproduces a frame 1102 that is rigid, but lightweight and consumes lessplastic or other fabrication materials. While the vertical grooves 1110are readily formed using a simple 2-part molding process, it may benecessary to use an side insert form the horizontal grooves 1108. Theneed for such additional molding steps and expense has been eliminatedin the embodiment of FIG. 11 by forming the horizontal groove 1108 instaggered segments. In this embodiment, upper faces formed on the bottomhalf of the mold form the downward-facing portions (i.e., the upperedge) of the horizontal groove 1108, and downward faces of the uppermold half form the upward facing portions (i.e., the lower edge) of thehorizontal groove 1108. Of course, any other suitable manufacturingmethod may be used in other embodiments.

The grooves 1108, 1110 on the ETU 1100 correspond to similar structureson a gripper 1200, shown in FIG. 12, that is used to move and manipulatethe ETU 1100. As shown in FIG. 12, the exemplary gripper 1200 comprisestwo opposed jaws 1202 that can be moved together when necessary to graspthe ETU 1100 along its long sides. As with other grippers describedherein, one or both jaws 1202 may be moveable by any suitable means,such as a servo-motor or pneumatic or hydraulic drive piston, and thegripper 1200 may have alternative shapes and constructions. The jaws1202 also may simply be spring loaded to flex over and clamp onto theETU by spring force, in which case some kind of clamp or other grippingmember may be used to hold the ETU when its desired to release it fromthe jaws 1202, or the jaws 1202 may include an actuator that forces themopen to release the ETU. Other variations will be readily apparent inview of the present disclosure.

Each jaw 1202 has a horizontal rib 1204 and a vertical rib 1206. Thehorizontal ribs 1204 are shaped and sized to extend into the horizontalgrooves 1108, and the vertical ribs 1206 are shaped and sized to extendinto the vertical grooves 1108. When so positioned, the gripper jaws1202 securely hold the ETU frame 1102. In addition, some or all of theribs 1204, 1206 and grooves 1108, 1110 may be chamfered, rounded orbeveled to help them fully and properly engage even if there is somemisalignment between the jaws 1202 and the frame 1102. An example ofsuch a chamfer is shown in the Figures. In this embodiment, the gripperand ETU are configures such that the jaws 1202 will realign and graspthe ETU 1100 even if they are misaligned by up to about 1 to 2millimeters. This helps to hold the ETU tightly during high speed motionand can tolerate a relatively large mismatch in ETU position. This keyedconfiguration may allows the grippers to operate without the use ofaddition of a compliant material which may be subject to wear, but itwill be understood that removing any compliant material is not requiredin all embodiments.

Exemplary ETU Transport Mechanism

As noted above, any suitable mechanism may be used to transport the ETUsthrough an exemplary processing system. For example, the ETUs in theembodiment of FIGS. 1 and 2 may be loaded into the PAS 100 a rack onthat holds the ETU 1100 by each end of the frame 1102. Such a rack mayhave any suitable springs, arms, conveyors and the like that move theETU 1100 along the rack from the input location 110, to the loadinglocation where it receives samples, to the output location where it istransferred by a transfer unit 224 to a processing area 226. Thetransfer unit 224 may comprise any suitable articulating mechanism, suchas known in the art, and may include jaws such as those described withrespect to FIG. 12, to grip the ETUs 1100. Once in the processing area226 one or more ETU movers may be used to convey the ETUs between thevarious processing stations. Where multiple ETU movers are used, themovers may operate on parallel tracks and each have access to allpositions or stations, or multiple movers may be provided on the same ordifferent tracks and have access to only some of the positions.

FIG. 13 illustrates one example of an ETU mover 1300 that may be used asa single unit that transfers all of the ETUs between the variousstations. The ETU mover comprises a gripper head 1302 that is connectedto a shuttle 1304 by a servo-operated machine screw 1306, hydraulic orpneumatic cylinder, or by any other suitable device, to allow the head1302 to move vertically with respect to the shuttle 1304. The shuttle1304 is movably connected to a track 1308 that is attached to the PASframe 1310 above the processing area 226, and provided with suitablemeans to traverse the shuttle 1304 laterally along the track 1308. Suchtraversing devices are well-known in the art and need not be describedhere. The gripper head 1302 includes a grip, such as the jaws 1202described above, for grasping and moving the ETUs.

In use, the ETU mover 1300 operates throughout the clock cycle to moveETUs from one station to the next. Typically, the ETU mover 1300 beginsat the last process (e.g., moving ETUs to a solid waste receptacle) tofree the last processing station, then progresses backwards through theflow path to move each ETU into the next position. The ETU moverpreferably completes all necessary ETU movements once per clock cycle.During startup and the last stages of operation during a shift, ETUs maynot be present at all stations. For example, the first ETU that isprocessed remains in the incubator for multiple clock cycles. Underthese circumstances, the ETU mover 1300 may be programmed to skipoperations, or it may simply continue to operate as if ETUs were in allof the stations. The latter option may be preferred to simplifyoperation and reduce the likelihood of errors.

Exemplary Magnets

FIGS. 14A and 14B show exemplary arrangements of magnets for use in anaspiration station, such as the first and second aspiration stations238, 240 described above. The depicted systems use multiple bar magnets1402 of the rare earth type (e.g., neodymium-iron-boron), but any othersuitable type of magnet may be used (e.g., electromagnets, ferricmagnets, ceramic magnets, plastic magnets, etc.).

The magnets 1402 are located on one side of the ETU tubes 1104 toattract paramagnetic beads inside the tubes 1104. While a single strongmagnet may be used for one or more tubes 1104, multiple magnets 1402 maybe used for each tube, or across a number of tubes. A crossbar 1404 maybe positioned opposite the magnets 1402 to help press the tubes 1104towards or against the magnets 1402. Typically, the magnet array has twoor more magnets depending on the volume of the paramagnetic beadsolution. To enhance the attraction of paramagnetic beads, a small spacemay be set between the magnets at the areas between adjacent magnets.The precise spacing may be maintained using an aluminum spacer. Thisarrangement helps to attract the beads along the wall of the tubequickly. The magnets 1402 may be arranged in any suitable manner. Forexample, the orientation as shown in FIG. 14A has the adjacent magnetsarranged North-to-North and South-to-South. This arrangement is believedto attract beads faster than the North-to-South arrangement shown inFIG. 14B, but either configuration may be used. Without being limited byany theory of operation, it is believed that the North-to-North andSouth-to-South orientation shown in FIG. 14A causes the magnetic fieldto extend further into the sample than a North-to-South orientation suchas is shown in FIG. 14B, resulting in greater attractive force andfaster attraction. Additional possible configurations include usingmagnets on both sides of the tube or surrounding the tube. Anotherconfiguration would use a magnetic probe inserted into the tube toattract the beads, which could then be either withdrawn or simply heldto allow liquid aspiration. For example, a magnetic probe could alsoinclude an aspiration inlet. Optionally a magnetic probe comprises amagnetic material that can be moved in an out of a sheath, such that thebeads are captured against the sheath and then released when the magnetis withdrawn. A magnetic or paramagnetic probe may be moved within thesample volume to increase the rate at which beads encounter the magneticfield and are pulled to the probe, causing faster attraction of thesample.

It has been found that bar magnets that are 6″ long×⅛″ tall by 5/16″deep may be used. The 6 inch length extends the entire length of anexemplary ETU 1100. Alternatively, two 3-inch magnets may be used end toend. Without being limited to particular sizes, the vertical thicknessof the magnets in the exemplary embodiment may comprise around a ⅛″minimum dimension, with the maximum being about the length of the testtube 1404, or about 3 inches.

Exemplary Aspirator Assemblies

FIGS. 15A and 15B illustrate an exemplary aspirator 1500 and aspiratorstation 1502 that may be used with various embodiments of the invention.The aspirator 1500 is mounted to an aspirator frame 1504 that isconnected to a suitable actuating arm 1506 to move the aspirator 1500laterally to various processing stations and vertically into and out ofthe ETU tubes 1104. The aspirator 1500 comprises an aspirator body 1508that is mounted to the aspirator frame 1504, a number of hollowaspirator tips 1510 that are shaped and sized to extend to the bottomsof the tubes 1104, and fittings 1512 that fluidly connect the tips 1510to one or more suction sources.

As noted above, the aspirator 1500 may be used during a processing stepin which magnets are used to attract magnetic beads in the tubes 1104.Such an arrangement is shown in FIG. 15B, in which the ETU 1100 ismounted in an aspirator station 1514 having openings 1516 through whichthe tubes 1104 are exposed to magnets (not shown). As such, if the tips1510 comprise a magnetic material, they could deflect during aspiration.To overcome this potential difficulty, the tips 1510 may be made ofInconel™ (Special Metals Corporation, New Hartford, N.Y.), an austeniticnickel-chromium-based superalloy. Other designs could employ othernonmagnetic materials, such as plastic, aluminum or austenitic steel,use magnetic materials having lateral reinforcement to avoid deflection,or be curved away from the magnet position such that deflection towardsthe magnets does not draw their openings away from the desired position.A non-wetting coating, such as Teflon™ (polytetrafluoroethylene) orceramic vapor, may be applied to the tips to reduce the likelihood ofcarryover from one sample to another.

One or more pumps (not shown) may be used for all of the tips 1510, buta configuration using a single pump may lose suction in some or all ofthe tubes when one tube is emptied. As such, in one embodiment, eachaspirator fitting 1512 may be connected to one head of a two-headedpump. Although this requires multiple pumps (e.g., four pumps for anaspirator having eight tips, as shown) This ensures that all of thetubes will be aspirated generally independently, even if one tube isemptied before others are, and provides greater independence ofoperation. During aspiration, the tips 1510 are pressed to the bottomsof the ETU tubes 1104. To at least partially accommodate slightvariations in the tube lengths or uneven placement of the ETU 1100, theaspirator body 1508 may be movably mounted on the aspirator frame 1504by one or more springs 1518 that allow the tips 1510 to conform to theETU position. The springs 1518 are captured between the aspirator body1508 and end caps 1520 to allow the aspirator body 1508 to move upwardsby compressing the springs 1518. In the shown embodiment, one spring1518 is provided at each end of the aspirator body 1508, which allowsthe aspirator body 1500 tips 1510 to rock along the length of the frame1506. While this amount of movement is believed to be suitable to obtainacceptable aspiration across an 8-tube ETU, in if greater accuracy ormore independent controls is desired the each aspirator tip 1510 orgroups of the tips 1510 may mounted on separate springs in otherembodiments.

Exemplary Final Transfer Unit and Methods

FIG. 16 depicts an example of a final transfer unit 1600 that may beused with exemplary embodiments to transfer processed samples from anETU to a sample tray. While the shown final transfer unit 1600 hasparticular application in a PAS, it may of course be used in othercontexts and with other systems and processes. The exemplary finaltransfer unit 1600 comprises a four-channel, fixed-separation pipettor1602 that is mounted on a moveable platform 1604. The pipettor 1602 canmount up to four pipette tips 1606, each of which is releasably andfluidly connected to a pipette channel 1610. To facilitate automation,the tips 1606 may be engaged by lowering the channels 1610 into the tips1606 and applying pressure to secure them together, and disengaged usinga motorized tip ejector 1612 that pushes on an ejector plate 1608 toslide the tips 1606 off the channels 1610. The relationship between theejector plate 1608 and pipette tips 1606 is shown in FIGS. 17A and 17B,which show the ejector plate having bores 1712 that are large enough topass over the pipette channels 1610, but small enough to abut and end ofthe pipette tip 1606 to push it off the channel 1610. Also shown inthese figures are channel tips 1714 that are attached to each channel1610 and comprise a deformable material disposed on its outer surfacethat compresses against an, inner surface of the pipette tip wheninserted, thereby securing the tip 1606 to the channel 1610 and creatinga suitable air-tight seal. Replaceable pipette tips and ejectors areknown in the art and need not be described in detail here.

As best shown in FIGS. 17A and 17 b, the pipettor channels 1610 may bemounted within respective bores 1702 through the pipette platform 1604.The channels 1610 can slide at least some distance along the bores 1702,but are captured in place by, for example, upper and lower retainerrings 1704, 1706, that prevent the channels 1610 from escaping the bores1702. A spring 1708 is captured between the lower retainer ring 1706 andthe pipette platform 1604 and is dimensioned to apply a restoring forcethat biases the channels 1610 downward, as shown in FIG. 17A. In use,these springs 1708 provide a degree of independent vertical movement foreach pipette channel 1610. When the pipettor 1602 is fully lowered intothe ETU 1100, such as shown in FIG. 17B, the springs 1708 mayindependently compress as the pipettor tips 1606 contact the bottoms1710 of each ETU tube 1104. Provided the spring travel distance on eachpipettor channel 1610 is sufficient to accommodate the difference intube lengths or any offset in the ETU, this independent movement shouldallow all of the pipettor tips 1606 to contact the bottom of theirrespective ETU tubes 1104. In this position, an over volume aspirationmay be performed, and there is significant assurance that all of thefluid in each tube will be aspirated.

The foregoing arrangement, or similar arrangements in which one or moretips may be independently moveable with respect to the others, may beparticularly helpful where the volume in the tubes may be small, andliquid level detection may not be suitable to assist with liquidtransfer. For example, in the PC and Surepath protocols discussed above,the final transfer unit 1600 transfers extracted nucleic acids containedin the ETUs to the corresponding column of a 96-well plate, however thevolume of the final concentrated nucleic acid solution may be less thanabout 100 ul. It has been found that, despite the low volume, the use ofindependently moveable pipettor tips 1606 enables consistent andcomplete transfer of such fluids. In this case, liquid level detection,which is difficult to implement when there is less than about 100 ulliquid in a tube, is not required.

Where the transfer volume is the same for all of the tubes, the finaltransfer unit 1600 may use a pipetting mechanism comprising a series ofair and/or liquid cylinders that are driven by a single motor or pump.In other embodiments, however, multiple pumps may be used to ensureaccurate aspiration and dispensing for each pipette.

Referring now to FIG. 18, an example of a manipulation system for anexemplary final transfer unit 1600 is shown. Here, the pipettor platform1604 is mounted to a first shuttle 1802 that is adapted to movevertically on a first track 1804. A servo-motor 1806 or any othersuitable drive mechanism may be used for this purpose. The first track1804 is, in turn, mounted to a second shuttle 1808 that is laterallymoveable along a second track 1810 by its own motor 1812. The secondtrack 1810 is mounted to a third shuttle 1814, which is laterallymoveable along a third track 1816 in a direction perpendicular to thesecond track 1810. A third motor 1818 is provided to control themovement of the third shuttle 1814. The foregoing arrangement providesthree dimensional movement for the final transfer unit 1600. If desired,mechanisms may be provided to control rotation about any axis. Inaddition, in other embodiments, different mechanisms and control devicesmay be used to manipulate the final transfer unit 1600 though itsdesired range of motion. For example, it may not be necessary to providemovement along one horizontal axis in the embodiment of FIGS. 1 and 2,in which case the third shuttle, track and motor may be omitted. Othervariations will be readily apparent in view of the present disclosure.

In order to complete the final transfer operation, the final transferunit 1600 must move samples from the relatively large and widely-spacedETU tubes into the relatively small and narrowly-spaced wells of atypical sample plate. One way to accomplish this may be to use a“varispan” arrangement, in which the width between the pipettor tips canbe varied. This requires additional mechanisms and controls, but ispossible in some embodiments. It has been found that, by properlyselecting the distances between the pipette tips and ETU tubes and usinga unique transferring protocol, the use of varispan pipettors may not benecessary. This may simplify the design, reduce costs, and improvereliability by eliminating a potential point of failure. Examples ofthis construction and protocol are shown in FIGS. 19A-19D, which areschematic diagrams illustrating two exemplary sample transfer operationsin which samples are transferred from an exemplary extraction tube unitto a standard sample plate using fixed-width pipettors.

In the exemplary embodiment, the final sample plates comprise standard96-well plates 208 in which the wells are spaced about 9 mm apart. TheETU tubes are spaced about 18 mm apart, which is twice the distancebetween the wells. In a first step, shown in FIG. 19A, the finaltransfer unit aspirates liquid from four adjacent tubes 1104 on the ETU1100, and deposits the liquid into four alternating wells 1900 in thesample plate 208. In the next step, shown in FIG. 19B, the finaltransfer unit aspirates liquid from the other four adjacent tubes 1104on the ETU 1100, and deposits the liquid into the other four alternatingwells 1900 in the same row of sample plate 208. As explained above,after each step, the final transfer unit may discard the used tips intothe empty ETU tubes to reduce solid waste volume. In an alternativeembodiment, shown in FIGS. 19C and 19D, a similar process is used totransfer liquid from a twelve-tube ETU 1902 to the 12-row side of astandard 96-well plate, using a six-channel fixed-width pipettor. Tofacilitate these embodiments, the distance between centers of adjacentETU tubes are approximately equal to a whole multiple “N” of thedistances between adjacent positions in the output container. Transferof all ETU samples can be performed by a fixed-width pipettor in Ntransfers. Moreover, both the number of tubes in an ETU and the numberof positions in a column in the output container are divisible by N,such that all positions in an output container are used. It will beunderstood that the capacity of an ETU and the capacity of a column inthe output container need not be equal; rather, all positions in the ETUtube can be drawn and all positions in the output container can befilled with a fixed-width multi-channel pipettor, as long as the numberof channels is a common divisor of (a) the number of positions in acolumn in the ETU tube, and (b) the number of positions in a column inthe output tray divided by N. It will also be appreciated that, in otherembodiments, the distance between adjacent tubes may be any wholemultiple of the distance between adjacent wells in a sample plate. Forexample, a fixed-width, two-channel pipettor can be used to transferfluid from a six-tube ETU to a plate having six wells, provided thespacing between the tubes is either three times the spacing between thewells. Other variations will be understood in view of the presentdisclosure without undue experimentation.

Alternative Exemplary Processing System

An alternative exemplary processing system is shown in FIG. 20. In thisembodiment, the system 2000 is provided in a generally lineararrangement. Samples are provided in ETUs, and conveyed through thesystem by a six-axis ETU mover 2004. As shown in FIG. 21, the ETU mover2004 has two grippers 2006, on opposite sides of a central column 2102.The central column rotates 180 degrees or more on a pedestal 2104, topermit the grippers 2006 to swap positions when needed. Each gripper2006 is mounted on shuttle 2106, which, in turn, is mounted on arespective vertical track 2108. Suitable linear actuators 2110 areprovided to move the grippers 2006 up and down, as required duringprocessing. If desired, an angular actuator 2116 or other linearactuators may be provided to give the grippers 2006 even greatermaneuverability. The entire ETU mover 2004 is mounted on a track 2112and a linear actuator 2114 is provided to move the ETU mover 2004 backand forth along the track 2112.

Referring back to FIG. 20, the processing stations are arrangedgenerally along a linear axis, with the ETU mover 2004 and its track2112 located between the stations. During operation, the ETU may beginat the ETU station 2008 with two empty grippers, pick up a new ETU inone gripper, move to the first processing station 2010, pick up the ETUat that station, turn, and deposit the new ETU into that station. TheETU mover 2004 then carries the ETU it retrieved from the firstprocessing station 2010, moves to the next station 2012, retrieves theETU at that station 2012, and turns and deposits the ETU from the priorstation 2010 into that station 2012. This process continues in thismanner until all of the necessary ETUs are moved. The ETU preferablycompletes all of the transfers during the course of one clock cycle. Inone embodiment, the clock cycle may be about 2 minutes, but other cyclesare possible.

The processing stations may include an ETU supply station 2008, a firstmixing station 2010, a second mixing station 2012 having threesubstations 2012 a, 2012 b, 2012 c, an incubation station 2014 havingmultiple substations 2014 a, 2014 b, and aspiration station 2016 havingtwo substations 2016 a, 2016 b, and a final transfer station 2018. Thesestations may operate like the ones described with respect to FIG. 2, orin other ways, as will be appreciated in view of the present disclosure.The system also may include various reagent dispensing arms 2020, anaspirator 2022 and a final transfer unit 2026, such as those describedpreviously herein or according to other constructions. Waste containers2024 and reagents also may be provided, such as described elsewhereherein.

As with previously discussed embodiment, some of the stations mayinclude multiple substations or slots to hold ETUs for multiple cycles.A simplified version of this embodiment may eliminate the rotary axis,in which case the two grippers 2006 and all of the processing stationsmay be arranged on one side of the track 2112. A further simplifiedversion of this system may have only one vertical movement component. Inthis embodiment, which is similar to the one described above withrespect to FIG. 13, the robot may start from the last processing stepand pick up ETUs from the previous processing slot and loads them to thecurrent processing slot. Again, this is repeated for all the processingsteps in about a 2 minute interval, but other intervals may be used.

Sample Tracking/Barcode Integration

As noted above barcoding or other identification technology may beintegrated into various embodiments of processing systems. In theexemplary embodiment of FIG. 1, barcoding may be used extensively toidentify samples, track the samples' location on input, output andintermediate processing containers (such as ETUs and output sampleplates), and generally help assure quality control. For example, allsample bottles loaded in each sample rack may be barcoded, and thebarcode is read as each sample is initially accessed. This can be usedto guarantees both that the system identifies the sample as being onethat is intended to be tested in the system, and that the sample can beidentified for processing. Using this protocol, a sample may be placedin the reject tray if it is recognized, but determined to be a sampleintended for some other process, or not recognized due to an unknown ormissing barcode. The system may receive information about whether aparticular barcode is to be analyzed from the CCU or another computersystem or data file. If a sample with an unknown of missing barcode canbe otherwise identified, it may be barcoded and processed. The systemalso may be operated in a forced testing mode that allows samples to beprocessed whether or not a barcode is recognized.

Reagents also may be barcoded. Preferably, the lot numbers and/orexpiration dates of reagents are coded into the barcode and recognizedby the system. Optionally (such as if local regulations require),barcodes may be used to ensure that old reagents are completely flushedwhenever a new reagent is added from a new lot to prevent mixing oflots. Barcode tracking also may be used to better track reagent usage,and ensure that expired reagents are not used. A barcode scanner for thereagents may be provided, for example, in the chamber that holds thereagent, as a separate device, or as a scanner that is flexiblyconnected to the system by a tether or electric cord.

In one preferred embodiment, each ETU may be barcoded. The ETUs may bescanned before, as or after the samples are added to them, and a map maybe generated to associate the samples to their particular locations(i.e., tubes) in the ETU. The ETU may be scanned again just before thesamples are transferred to a 96-well plate or other output vessel.Additional scans may be performed at other locations. This providesfurther assurance of proper machine operation and a lack of outsideinterference, and helps confirm that each ETU has been fully processedthrough all process steps and that each sample in the output trayexactly corresponds to the expected sample. Barcoding the ETU or othersample processing containers also may permit recovery of a machine thatfails or is interrupted during operations, by allowing either automatedor manual scanning to associate each sample with its particular stage ofprocessing. In such a system, it may be possible to precisely resumeprocessing for each sample either after the machine is repaired orotherwise returned to operating condition, or by transferring thesamples to a working machine or by continuing the processing manuallyfrom the last processing operation.

In addition, each 96-well plate may be barcoded and scanned before,during or after samples are transferred to it. This may be done torelate each sample from the ETU (and, by correlation, from each samplecontainer) to a particular plate position via a map that is generated bythe system and transmitted to a central control unit.

Other components, such as the sample racks, also may be barcoded totrack their use or movement, or to identify their contents.

Any suitable barcode readers may be used to scan the various barcodes,and such readers may be located at any suitable location. For example, abarcode reader may be placed in a fixed position, with barcodes beingread as they are moved past the reader. In other embodiments, a barcodereader may be attached to a robotic arm, which may be moved to permitscanning of samples from different positions and angles. In otherembodiments, a barcode reader may be attached to a robotic arm or othermechanism that transports the object, in which case the barcode readermay scan the object as it is being transported. Such devices may holdthe object on a rotating or moving platform that repositions the objectto bring the barcode within sight of the reader. For example, a rotatinghead that holds an object may facilitate barcode reading with a fixedbarcode reader or with a barcode reader attached to a robotic arm. Otherexemplary embodiments employ mirrors and/or other optics to permitscanning of barcodes in different locations, on objects situated atdifferent angles, on objects located at different distances from areader, and so on.

The construction and operation of suitable barcode readers are wellknown in the art, and need not be explained in detail here. It will beunderstood that any linear, omni-directional, 2-dimensional,holographic, pattern recognition, or other scanning system and formatmay be used. Furthermore, as used herein, the term “barcode” alsoencompasses not only any and all optical identification systems, butalso non-optical systems, such as radio-frequency identification (RFID)systems. RFID systems may include an RFID tag and a reader, which may beemployed in similar ways to optical barcodes, except that a line ofsight may not be required. Methods known in the art may be used to avoidthe ambiguities potentially created by the omnidirectional nature of theRFID signal, such as use of directional antennae for transmission orreceipt of signals; use of systems effective only at short-range(permitting disambiguation through signal attenuation or throughdecreasing the number of tags within range of the receiver); use of RFIDtags for objects of a type that are unique within a system; or use ofRFID tags together with other spatial information (e.g., an RFID tagassociated with an entire sample rack, together with known informationabout which sample is in which position in the rack).

Clinical Example 1

An exemplary embodiment was operated to process liquid based cytologyspecimens using Qiagen's Next Generation Hybrid Capture® High Riskassay. The system was adapted to accommodate specimens in PreservCyt®(PC) medium in the existing Hybrid Capture 2 (HC2) assay, which requiressample volumes of 4 mL. The pre-analytical system was developed toproduce up to ten 96-well plates of extracted DNA in less than 5 to 6hours for subsequent analysis in the Next Generation Hybrid CaptureAssay® (NGA) (see U.S. Provisional Application 61/108,687 filed Oct. 27,2008). From system start-up, the first fully processed plate wasproduced in 59 minutes with subsequent plates available every 24 min.The objective for this study was to compare manual nucleic acidextraction method from 1 ml of PC samples with the high-throughputautomation method for recovery, carryover, throughput andreproducibility of HPV DNA processed.

In this example DNA-extraction chemistry was used in an automatedversion of the manual process of sample conversion (extracting nucleicacid from a cytology sample). HC2-positive PC specimens were spiked intopooled HC2-negative specimens and replicate aliquots were processed inthe sample prep processing instrument or manually. Recovery wasdetermined by comparative HC2 signal output from each method. Carryoverwas assessed by measuring the RLU/CO of negative specimens that wereprocessed just before and just after a high positive specimen.Intra-plate reproducibility was measured with plasmid introduced intothe sample preparation process and compared to plasmid tested directlyin the NGA. Inter-plate reproducibility was measured by comparing knowncopies of HPV plasmid DNA processed from 10 plates.

In two separate runs of a PC positive clinical pool, (n=32 replicateseach run) the percent signal recoveries from the automated method were99% (9% CV) and 93% (6% CV). Results from negative pools run through theautomated system were also comparable to those manual method results:the RLU/CO of the manually processed clinical pools (n=8) compared toautomated-processed pools (n=40) from three separate runs were: 0.27 to0.26 (11% CV); 0.28 to 0.32 (20% CV); and 0.31 to 0.27 (15% CV). Incarryover measurements, the average RLU/CO difference between negativespecimens that were processed before (n=40, 16, 12) and after (n=40, 40,52) a high positive were minimal: 0.26 to 0.32 (20% CV); 0.32 to 0.30(20% CV); and 0.32 to 0.37 (32% CV). In another target carry-over study,10̂8 copies of HPB16 DNA were added into a negative sample panel, and itwas shown that neighboring samples did not give a positive signal.Intra-plate and inter-plate reproducibility was very good with low CV.Processing of 80 replicates of either negative or positive (HPV 16 DNA)samples showed very low sample-to-sample variability (CV 12% fornegative samples and 5% for positive samples). High reliability and lowvariability of the magnetic beads was demonstrated by employing severallots of magnetic beads and observing comparable signal levels (RLU/COvalues) between lots. Ten plates of individual clinical PC specimenswere successfully run through the automated system in a continuousfashion in just over 4.5 hours.

This integrated system in this embodiment is believed to be particularlyadvantageous due to the low throughput of manual sample conversionprotocol.

Clinical Example 2

A fully automated Next Generation Hybrid Capture® HPV DNA assay wasperformed on an automated analytical system. It was found that theanalytical sensitivity for the automated system was 1875 copies (95% CI1615-2290) of HPV 16 plasmid, as compared to 1950 copies (95% CI1650-2800) of HPV 16 plasmid in the manual assay. Assay specificity wasevaluated with 22 HPV LR types in the Next Generation Hybrid CaptureAssay® (NGA) (see co-pending provisional application 61/108,687 filedOct. 27, 2008, which is incorporated by reference herein) assay andcompared to the current HC2 HPV DNA Test. All 22 HPV LR types weretested at a high concentration of 2.0 ng/mL. Results of the analyticaltesting show that the number of HPV low risk types that cross-hybridizewith the NextGen assay is significantly reduced as compared to HC2assay. Clinical specimens with 30% prevalence rates were used toevaluate the performance between the automated system and manual assays.The total, positive and negative agreements were 96% (95% CI 89-98%),85% (95% CI 64-95%), and 99% (95% CI 7498%), respectively. The Kappavalue was 0.87 for this study. The assay reproducibility on theautomated system was improved over the manual assay using HPV 16plasmids. The fully automated assay had consistent performance fromplate to plate and day to day. No indication of target carryover wasfound when samples containing up to 7.5×10̂5 copies/ml of HPV DNA type 16were processed on the automatic system.

Overall the analytical and clinical data presented is believed to showthat the fully automated Next Generation Hybrid Capture® HPV DNA assayon an automated analytical system can significantly improve assayspecificity and assay reproducibility without compromising sensitivityof detection of HR virus. The automated system provides also fullautomation of the next-generation hybrid capture HPV DNA assay with ahigh throughput.

Clinical Example 3

In this study evaluated a novel extraction protocol that is compatiblewith various collection media and amenable to high throughputautomation. A standard and reproducible HPV DNA test method that usesresidual samples from SurePath media has not been previously reported.Most methods use cumbersome procedures and longer lysis incubation time,which is not suitable for high volume lab workflow. The desiredextraction chemistry preferably takes no more than about 60 minutes forprocessing 96 samples and may be compatible with the ultra-highthroughput next generation Hybrid Capture® system QIAensemble SP fromQiagen. A universal extraction chemistry protocol was developed for usewith both PerservCyt and SurePath liquid based media.

In this study, the novel sample processing chemistry was evaluatedagainst the industry standard: Digene Hybrid Capture® 2 High-Risk HPVDNA Test® method. HPV16 positive SiHa cells (20,000 cells) were spikedinto 4 mL of negative PC clinical specimen pool processed using astandard HC2 manual conversion method. The same amount of SiHa cellswere spiked into a 1.5 mL PC pool and processed by the new extractionprotocol. The same volumes of Surepath® HPV positive and negativeclinical pools by HC2 were tested by both sample processing methods.Assay protocols are illustrated in FIG. 22. The centrifugation step maybe performed as part of an automated system or manually. DNA eluatesgenerated by both methods then were then re-tested side-by-side by theHC2 method. Recovery was determined by comparative HC2 signal outputfrom each method. The new chemistry protocol was integrated withprototype instrumented and performance was evaluated with the HC2 methodby testing individual clinical specimens.

Referring now to FIGS. 23-25, the results with PC positive and negativepool show similar performance by both sample processing protocols withno increase in the background signal (left column in each group is thereference method; right column in each group is the test method). InSurePath® samples, the new extraction method resulted in a 3.5 foldincrease in signal relative to the standard HC2 method (“SP-Pos clinicalpool”), relatively low background with negative samples (“SP-Negclinical pool”) and good reproducibility. The new method showed 93% DNArecovery when compared to direct DNA input in HC2. The individualSurepath® clinical specimens (n=160) processed by NextGen automation andcompared with HC2 manual process showed a greater than 90% assayagreement. This study is believed to established a novel universalprotocol and automation solution for HPV DNA test with residualliquid-based cytology (LBC) specimens and demonstrates high throughputcompatibility by processing 96 samples in 60 minutes. These resultsadditionally demonstrate the flexibility of the automated systemsprovided herein.

While the invention has been described by way of examples and preferredembodiments, it is understood that the words which have been used hereinare words of description, rather than words of limitation. Changes maybe made, within the purview of the appended claims, without departingfrom the scope and spirit of the invention in its broader aspects.Although the invention has been described herein with reference toparticular means, materials, and embodiments, it is understood that theinvention is not limited to the particulars disclosed. The inventionextends to all equivalent structures, means, and uses which are withinthe scope of the appended claims.

1. (canceled)
 2. A continuous-loading sample processing systemcomprising: a sample input adapted to receive at least one samplecontainer rack manually provided by a user; a consumable input adaptedto receive one or more unused consumable supplies manually provided by auser; a waste output adapted to receive used consumable supplies; anautomated processing center comprising: a decapper adapted to remove alid from at least one sample container provided in the at least onesample container rack, a pipettor adapted to remove a specimen from theat least one sample container and transfer the specimen to at least oneoutput vessel, and a capper adapted to replace the lid on the at leastone sample container; a sample output adapted to receive the at leastone output vessel and present the at least one output vessel to a userfor manual removal.
 3. The system of claim 2, wherein the decapper andthe capper comprise at least one combination decapper/capper unitadapted to remove the lid from the sample container and replace the lidon the sample container.
 4. The system of claim 3, wherein the decapperand the capper comprise two combination decapper/capper units.
 5. Thesystem of claim 4, wherein the sample output comprises at least oneoutput rack adapted to receive a plurality of output vessels.
 6. Thesystem of claim 2, wherein the automated processing center furthercomprises a transfer arm adapted to remove the at least one samplecontainer from the sample container rack and place the at least onesample container in the decapper.
 7. The system of claim 2, wherein theautomated processing center further comprises at least one shakeradapted to shake the at least one sample container.
 8. The system ofclaim 2, wherein the automated processing center further comprises: atleast one shaker adapted to shake the at least one sample container; anda transfer arm system adapted to: remove the at least one samplecontainer from the at least one sample container rack and place the atleast one sample container in the at least one shaker; remove the atleast one sample container from the at least one shaker and place the atleast one sample container in the decapper; and remove the at least onesample container from the capper and place the at least one samplecontainer in the at least one sample container rack.
 9. The system ofclaim 8, wherein the automated processing center further comprises abarcode reader adapted to read any readable barcode on the at least onesample container.
 10. The system of claim 3, wherein the at least onecombination decapper/capper comprises: at least one bottle grip adaptedto hold a bottle portion of the at least one sample container; and atleast one cap grip adapted to hold the lid; wherein the bottle grip andthe cap grip are movable relative to one another to remove the lid fromthe bottle portion.
 11. The system of claim 10, wherein the at least onebottle grip comprises a bellows grip having a flexible bellows with avariable-size bore adapted to receive the bottle portion along an axisof the variable-size bore, and one or more ribs mounted on the flexiblebellows within and aligned with the axis of the variable-size bore. 12.The system of claim 10, wherein the at least one bottle grip is mountedon a platform, the platform being adapted to selectively move to a firstlocation accessible to the at least one cap grip, and a second locationaccessible to the pipettor, and further being adapted to tilt the bottleportion relative to a vertical axis at the second location.
 13. Thesystem of claim 2, wherein the at least one sample container rackcomprises one or more sample holders adapted to hold at least one firstsample container having a first size, and at least one second samplecontainer having a second size that is different from the first size.14. The system of claim 2, further comprising a reagent input adapted toreceive one or more unused reagents manually provided by a user.
 15. Thesystem of claim 14, wherein the automated processing center furthercomprises at least one reagent dispenser adapted to dispense at leastone of the one or more unused reagents into the at least one samplecontainer.
 16. A sample processing system comprising: a sample inputadapted to simultaneously receive a plurality of sample containers; aconsumable input adapted to receive one or more unused consumablesupplies; a waste output adapted to receive used consumable supplies; anautomated processing center comprising: a decapper adapted to remove alid from at least one sample container, a pipettor adapted to remove aspecimen from the at least one sample container and transfer thespecimen to an output vessel, and a capper adapted to replace the lid onthe at least one sample container; a sample output adapted to receivethe output vessel; and a user interface adapted to receive an input fromthe user to indicate the identity of the at least one sample container,and control at least one operation based on a physical property of theat least one sample container.
 17. The system of claim 16, wherein theplurality of sample containers comprises at least one first samplecontainer having a first size, and at least one second sample containerhaving a second size that is different from the first size.
 18. Thesystem of claim 16, wherein the sample input is adapted tosimultaneously receive a plurality of sample containers in a samplecontainer rack.
 19. The system of claim 16, wherein the sample containerrack comprises one or more sample holders adapted to hold at least onefirst sample container having a first size, and at least one secondsample container having a second size that is different from the firstsize.
 20. The system of claim 16, further comprising a reagent inputadapted to receive one or more unused reagents.
 21. The system of claim20, wherein the automated processing center further comprises at leastone reagent dispenser adapted to dispense at least one of the one ormore unused reagents into the at least one sample container.
 22. Ahybrid manual-automated method for processing samples, the methodcomprising: manually providing a plurality of sample containers in asample input; manually providing unused consumable supplies in aconsumables input; automatically removing a lid from each samplecontainer using an automated system; automatically withdrawing aspecimen from each sample container using the automated system;automatically transferring the specimen to an output vessel using theautomated system; automatically replacing the lid on each samplecontainer using the automated system; automatically conveying the outputvessel to an sample output location using the automated system; andmanually removing the output vessel from the sample output location. 23.The method of claim 22, further comprising programming the automatedsystem to control at least one operation based on a physical property atleast a first sample container.
 24. The method of claim 23, whereinprogramming the automated system comprises manually programming theautomated system.
 25. The method of claim 22, further comprisingprogramming the automated system to control at least one operation in afirst manner based on a physical property at least a first samplecontainer, and in a second manner based on a physical property of atleast a second sample container.
 26. The method of claim 22, wherein theplurality of sample containers comprise at least one first samplecontainer having a first physical dimension and at least on secondsample container having a second physical dimension that is differentfrom the first physical dimension.
 27. The method of claim 22, furthercomprising manually providing one or more unused reagent in a reagentinput, and automatically dispensing at least one of the one or moreunused reagents into at least one sample container.